Both Ipamorelin and CJC-1295 peptides are grouped within this category, investigated for their supposed similar physiological effects, although they appear to differ primarily in their half-life and pharmacokinetic properties.

CJC-1295 Peptide

CJC-1295 peptide represents a tetra-substituted derivative of growth hormone-releasing hormone (GHRH) 1-29, devised to mimic the shortest functional sequence of GHRH. GHRH 1-29 encompasses the initial 29 amino acids of the native GHRH peptide and holds the potential to stimulate growth hormone production within somatotrophs, the pituitary gland cells. The peptide undergoes four amino acid substitutions, strategically positioned within its structure, which researchers hypothesize may bolster its activity and resilience against proteolytic degradation. Specifically, the substitutions are situated at the 2nd, 8th, 15th, and 27th amino acid positions.

These alterations potentially enable the peptide to covalently bind to blood albumin, with incidental interactions possibly occurring with fibrinogen and immunoglobulin G (IgG). Consequently, the reported half-life of the peptide may possibly extend from 10 minutes to approximately 30 minutes.^[3] This elongated half-life may culminate in heightened levels of plasma growth hormone and insulin-like growth factor 1 (IGF-1).

Furthermore, CJC-1295 is speculated to incorporate a “drug affinity complex” (DAC) component, which may associate with plasma proteins. Specifically, the DAC element within CJC-1295 pertains to the attachment of N-epsilon-3-maleimidopropionamide derivative of lysine at the C-terminal end. By amalgamating the tetra-substituted amino acid chain with the DAC element, CJC-1295 may exhibit improved pharmacokinetic properties while preserving a comparable affinity to the GHRH receptors within the pituitary gland, akin to endogenous GHRH.^[4]

Ipamorelin Peptide

Ipamorelin is a synthetically engineered pentapeptide believed to interact with the growth hormone secretagogues receptor (GHS-R1a) situated in pituitary gland cells. These receptors, primarily localized in the hypothalamus, are commonly referred to as ghrelin receptors due to the apparent affinity of ghrelin as their primary endogenous ligand. Ipamorelin distinguishes itself among other growth hormone secretagogues (GHSs) as a potentially more selective compound. It is hypothesized to selectively stimulate the release of growth hormone (GH) levels from somatotroph cells without concomitant elevation of other hormones produced by the anterior pituitary gland, such as prolactin.

When the peptide blend, also denoted as the peptide stack, is introduced in combination, studies indicate that Ipamorelin typically initiates first action, purported exhibiting discernible impact within the initial two hours of exposure. Subsequently, as the Ipamorelin effect diminishes, the CJC-1295 peptide may progressively contribute to the alleged physiological actions.^[5]

CJC-1295 & Ipamorelin Peptide Blend and Growth Hormone Levels

In a clinical trial^[6] conducted in the early 2000s, research subjects were allocated into two groups: one receiving a placebo and the other exposed to CJC-1295 peptide. Blood samples taken before and after the peptide exposure revealed a substantial increase, approximately 7.5-fold, in growth hormone pulsatility levels in the CJC-1295 group compared to the placebo group. Additionally, beyond its apparent influence on growth hormone synthesis, CJC-1295 reportedly “caused an increase in total pituitary RNA and GH mRNA, suggesting that proliferation of somatotroph cells had occurred, as [noted] by immunohistochemistry images.”

The underlying mechanisms of CJC-1295’s potential reportedly involve its interaction with specific binding sites on the growth hormone-releasing hormone (GHRH) receptor protein, possibly triggering conformational changes and initiating intracellular signaling cascades.^[7] This interaction is speculated to activate G-proteins, which, in turn, may lead to the generation of secondary messengers like cyclic adenosine monophosphate (cAMP) or inositol trisphosphate (IP3). These messengers further modulate cellular activities through protein kinases, ultimately influencing gene expression associated with growth hormone production.

Conversely, researchers suggest that Ipamorelin interacts with the N-terminus of the growth hormone secretagogue receptor (GHS-R1a) in anterior pituitary gland cells, forming non-permanent attachments through intermolecular forces such as hydrogen bonds and van der Waals forces. This interaction may potentially induce conformational changes in the receptor, initiating cell signaling pathways primarily involving G-proteins, notably Gαq/11.^[8] Activation of GHS-R1a may potentially trigger the activation of phospholipase C (PLC), leading to the production of secondary messengers like IP3 and diacylglycerol (DAG). IP3 release may lead to calcium ion (Ca2+) release from the endoplasmic reticulum, while DAG activates protein kinase C (PKC), ultimately facilitating the release of growth hormone from pituitary gland cells.^[9]

These findings suggest the intricate molecular mechanisms through which CJC-1295 and Ipamorelin may potentially modulate growth hormone secretion, providing valuable insights into their possible physiological effects.

Comparative Mechanisms of Action

Research investigations have been undertaken to ascertain the half-life and individual mechanistic actions of the two peptides – Ipamorelin and CJC-1295.

In a 1990s study^[5] with a concentration-escalation design, the levels of growth hormones were systematically monitored following each presentation of the peptides. The study’s findings suggested a singular episode of growth hormone release, reaching its zenith at 0.67 hours, followed by an exponential decline, supposedly due to negligible concentrations. This investigation concluded that Ipamorelin appears to exhibit a short half-life of approximately 2 hours, with potential actions tapering off thereafter.

In contrast, CJC-1295 was suggested to host a notably protracted half-life. Researchers noted that a single introduction of the peptide appeared to have led to sustained upregulation of growth hormone production by somatotrophs, purportedly contributing to an overall increase in growth hormone secretion by 46%. Another publication reported potential increases in growth hormone concentrations by “2- to 10-fold” and estimated the half-life of CJC-1295 to range between 5.8 to 8.1 days.^[11]

Ipamorelin & CJC-1295 Peptide Blend and Lean Mass

The interaction between CJC-1295 and Ipamorelin in stimulating growth hormone production by somatotroph cells in the anterior pituitary gland appears to yield a synergistic effect, potentially resulting in a positive nitrogen balance and increased lean mass in experimental models. A study^[11] aimed to elucidate the metabolic potential of Ipamorelin focused on hepatic markers associated with alpha-amino-nitrogen processing during artificially-induced catabolism.

Researchers investigated the liver’s capacity to produce urea-N (CUNS), serving as an indicator of nitrogen processing within the organ. They assessed the mRNA levels associated with enzymes of the urea cycle, evaluated overall nitrogen equilibrium, and estimated nitrogen distribution across various organs. Ipamorelin exposure was hypothesized to lead to a notable 20% reduction in CUNS compared to the catabolic state induced experimentally. Additionally, it was suggested that Ipamorelin might decrease the expression of urea cycle enzymes, restore nitrogen equilibrium, and potentially modulate nitrogen levels in organs.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing.  Bodily introduction of any sort is strictly prohibited by law.  All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References:

1. Raun K, Hansen BS, Johansen NL, Thøgersen H, Madsen K, Ankersen M, Andersen PH. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998 Nov;139(5):552-61. doi: 10.1530/eje.0.1390552. PMID: 9849822. https://pubmed.ncbi.nlm.nih.gov/9849822/
2. Lucie Jette et al, hGRF1-29-Albumin Bioconjugates Activate the GRF Receptor on the Anterior Pituitary in Rats: Identification of CJC-1295 as a Long Lasting GRF Analog, ResearchGate, January 2005.
3. The Discovery of Growth Hormone-Releasing Hormone: An Update https://onlinelibrary.wiley.com/doi/full/10.1111/j.1365-2826.2008.01740.x
4. Jetté, L., Léger, R., Thibaudeau, K., Benquet, C., Robitaille, M., Pellerin, I., Paradis, V., van Wyk, P., Pham, K., & Bridon, D. P. (2005). 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(7), 3052–3058. https://doi.org/10.1210/en.2004-1286
5. Gobburu JV, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharm Res. 1999 Sep;16(9):1412-6. doi: 10.1023/a:1018955126402. PMID: 10496658. https://pubmed.ncbi.nlm.nih.gov/10496658/
6. Ionescu M, Frohman LA. Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog. J Clin Endocrinol Metab. 2006 Dec;91(12):4792-7. doi: 10.1210/jc.2006-1702. Epub 2006 Oct 3. PMID: 17018654. https://pubmed.ncbi.nlm.nih.gov/17018654/
7. Martin, B., Lopez de Maturana, R., Brenneman, R., Walent, T., Mattson, M. P., & Maudsley, S. (2005). Class II G protein-coupled receptors and their ligands in neuronal function and protection. Neuromolecular medicine, 7(1-2), 3–36. https://doi.org/10.1385/nmm:7:1-2:003
8. Yin, Y., Li, Y., & Zhang, W. (2014). The growth hormone secretagogue receptor: its intracellular signaling and regulation. International journal of molecular sciences, 15(3), 4837–4855. https://doi.org/10.3390/ijms15034837
9. Bill, C. A., & Vines, C. M. (2020). Phospholipase C. Advances in experimental medicine and biology, 1131, 215–242. https://doi.org/10.1007/978-3-030-12457-1_9
10. Martin, B., Lopez de Maturana, R., Brenneman, R., Walent, T., Mattson, M. P., & Maudsley, S. (2005). Class II G protein-coupled receptors and their ligands in neuronal function and protection. Neuromolecular medicine, 7(1-2), 3–36. https://doi.org/10.1385/nmm:7:1-2:003
11. Aagaard, N. K., Grøfte, T., Greisen, J., Malmlöf, K., Johansen, P. B., Grønbaek, H., Ørskov, H., Tygstrup, N., & Vilstrup, H. (2009). Growth hormone and growth hormone secretagogue effects on nitrogen balance and urea synthesis in steroid treated rats. Growth hormone & IGF research : official journal of the Growth Hormone Research Society and the International IGF Research Society, 19(5), 426–431. https://doi.org/10.1016/j.ghir.2009.01.001

Protirelin Essential Functions

Researchers suggested that Protirelin may mimic the characteristics of naturally-occurring thyrotropin-releasing hormone (TRH). TRH is considered the first well-characterized hypothalamic peptide and has been studied as a neuroendocrine element. This peptide appears to be widely distributed in different brain regions, alluding to its analogs’ potential within the context of conditions such as brain and spinal injuries, as well as CNS disorders like schizophrenia, Alzheimer’s disease, epilepsy, amyotrophic lateral sclerosis, Parkinson’s disease, depression, shock, and ischemia.

Protirelin appears to stimulate the release of thyroid-stimulating hormone from the anterior pituitary. Additionally, it may potentially also increase prolactin release. The peptide has been suggested to increase TSH levels rapidly, peaking, then proceeding to decline more slowly, returning to baseline levels after about three hours.

Scientific Studies on Protirelin

Research teams have evaluated the potential impacts of Protirelin in the context of spinocerebellar degeneration (SCD). This disease is manifested as a group of progressive neurodegenerative disorders affecting the spinal cord and cerebellum, vital central nervous system components. Research models of SCD ultimately exhibit a decline in motor function. The potential efficacy of the peptide within the context of SCD was assessed using the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS). Data from both these scoring matrices may indicate the effectiveness of Protirelin in ameliorating SCD.^[1]

Thyrotropin releasing hormone (TRH), the smallest peptide hormone, is considered to exhibit central effects beyond its endocrine potential by acting on the pituitary-thyroid axis. It has been suggested to hold potential within the context of various neurological disorders, including intractable epilepsy. Research has been conducted to evaluate this peptide within the context of conditions like West syndrome, Lennox-Gastaut syndrome, and myoclonic epilepsy. Protirelin’s hypothetically prolonged action suggests a unique anticonvulsant mechanism, potentially influencing the seizure network’s plasticity.^[2]

Case Studies of Protirelin

In a randomized, single-blind, placebo-controlled study, research models of chronic upper motoneuron syndrome due to ischemic cerebrovascular lesions were exposed to a Protirelin tartrate. A semiquantitative assessment was used to identify a homogenous sample population, focusing on weakness and spasticity and neurophysiological evaluations (F-waves, magnetic motor evoked potentials). Results suggested a statistically significant absolute improvement in spasticity and muscular strength following the Protirelin tartrate, particularly in the lower limbs. The compound also exhibited supposedly favorable modifications in the response of the biceps femoris muscle to transcranial magnetic stimulation, including reappearance, increased amplitude, and a reduction in the motor-evoked potential threshold.^[3]

Exposure of L-pyroglutamyl-L-histidyl-L-prolinamide (protirelin) to research models of amyotrophic lateral sclerosis (ALS), appeared to result in an improvement in functions associated with a deficiency in both lower motor neurons (weakness) and upper motor neurons (spasticity). This improvement appeared to be sustained during the infusion and persisted for about 1 hour post-infusion, with occasional slight improvements even 20 hours later. The mechanism by which Protirelin may produce this action, whether by replacing an ALS-associated deficiency or acting as a symptomatic supplement, remains uncertain. This study suggests the potential of further TRH study within the context of ALS, and offers insights into its potential pathogenesis, opening avenues for further exploring this biomolecule.^[4]

Researchers hypothesize that Protirelin is also involved in elevating prolactin plasma levels, which may potentially influence sexual drive and function. As such, elevation in prolactin with Protirelin may contribute to modulating central nervous system centers regulating sexual drive and behavior.^[7]

Conclusions

Protirelin is a synthetic analog of the TRH neuropeptide. As outlined above, researchers speculate that the peptide’s impact may be diverse, the most prominent being neuroprotective potential in several neurodegenerative diseases. This peptide appears to be widely distributed in the hypothalamus region and may potentially manifest mitigatory action in refractory epilepsy, amyotrophic lateral sclerosis, motoneuron syndrome, and spinocerebellar degeneration.^[8]

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing.  Bodily introduction of any sort is strictly prohibited by law.  All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References

1. Yoshida A, Yamanishi Y, Tada S, Miyaue N, Ando R, Nagai M. Comparison of therapeutic effectiveness with SARA and iCARS using protirelin for spinocerebellar degeneration’s patients. Neurological Therapeutics. 2022;39(5):803-807. doi:10.15082/jsnt.39.5_803
2. Takeuchi Y. Thyrotropin-Releasing Hormone (Protirelin). CNS Drugs. 1996;6:341–350. https://doi.org/10.2165/00023210-199606050-00001
3. Civardi C, Naldi P, Cantello R, Gianelli M, Mutani R. Protirelin tartrate (TRH-T) in upper motoneuron syndrome: a controlled neurophysiological and clinical study. Ital J Neurol Sci. Nov 1994;15(8):395-406. doi:10.1007/BF02339903, PMID: 7875957, https://pubmed.ncbi.nlm.nih.gov/7875957/
4. Engel WK, Siddique T, Nicoloff JT. Effect on weakness and spasticity in amyotrophic lateral sclerosis of thyrotropin-releasing hormone. Lancet. Jul 9 1983;2(8341):73-5. doi:10.1016/s0140-6736(83)90060-0, PMID: 6134961, https://pubmed.ncbi.nlm.nih.gov/6134961/
5. Eandi M, Signorile F, Rubinetto MP, Genazzani E. [Evaluation of the efficacy and tolerability of protirelin. Results of a multicenter study in Italy]. Ann Ital Med Int. Jul-Sep 1990;5(3 Pt 2):270-8. Valutazione dell’efficacia e tollerabilita della protirelina. Risultati di uno studio policentrico in Italia. PMID: 2127689, https://pubmed.ncbi.nlm.nih.gov/2127689/
6. Marangell LB, George MS, Callahan AM, Ketter TA, Pazzaglia PJ, L’Herrou TA, Leverich GS, Post RM. Effects of intrathecal thyrotropin-releasing hormone (protirelin) in refractory depressed patients. Arch Gen Psychiatry. Mar 1997;54(3):214-22. doi:10.1001/archpsyc.1997.01830150034007, PMID: 9075462, https://pubmed.ncbi.nlm.nih.gov/9075462/
7. Kruger TH, Haake P, Haverkamp J, Kramer M, Exton MS, Saller B, Leygraf N, Hartmann U, Schedlowski M. Effects of acute prolactin manipulation on sexual drive and function in males. J Endocrinol. Dec 2003;179(3):357-65. doi:10.1677/joe.0.1790357, PMID: 14656205, https://pubmed.ncbi.nlm.nih.gov/14656205/
8. Alvarez-Salas E, Garcia-Luna C, de Gortari P. New Efforts to Demonstrate the Successful Use of TRH as a Therapeutic Agent. Int J Mol Sci. Jul 4, 2023;24(13) doi:10.3390/ijms241311047, PMID: 37446225 PMCID: PMC10341491, https://pubmed.ncbi.nlm.nih.gov/37446225/

Regarding the isolation, purification, and preparation of Thymosin Alpha 1, it was initially isolated from the calf thymus in 1977. However, a solid-phase synthesis technique in which molecules are covalently bound to a solid material is predominantly used for its commercial production. With the arrival of molecular expression methods, Ta1 is also being produced through prokaryotic and eukaryotic expression methodologies.

Thymosin Alpha 1 Overview

The synthetic analog of Thymosin Alpha 1, namely Thymalfasin, is primarily studied in research models of hepatitis B and C infection. It has the following amino acid sequence:

Ac–S–D–A–A–V–Asp–T–S–S–E–I–T–T–K–D–L–K–E–K–K–E–V–V–E–E–A–E–N–OH.

As described above and shown in the sequence, the peptide is N-terminally acetylated, has a net positive charge, and lacks stable conformation.

Several research institutions and teams have aimed to explore the breadth of the peptide’s potential. However, the mechanisms by which this peptide exerts its effects are an active area of investigation. Scientists believe that Thymosin Alpha 1’s potential in overcoming infections, cancer, immunodeficiency, and cell aging, may be through pleiotropic action. A recent study suggested that Thymosin Alpha 1 interactions with an oligosaccharide binding protein, Galectin -1 (Gal-1), are necessary to activate its potential ^[1].

The immunostimulatory effects of Thymosin Alpha-1 peptide are supposed to be mediated through Toll-like receptors (TLRs). It has been observed that Thymosin Alpha 1, through its binding with TLR3/4/9, appears to stimulate interferon regulatory factor (IRF3) and NF-kB signaling pathways. The ultimate effect is reflected in the immune-enhancing potential for both innate and adaptive immune system machinery. The immunomodulation against viral infections also appears to be mediated through activating T cells, B cells, macrophages, and Natural Killer cells ^[2].

The molecular mechanisms underlying the potential of Ta1 in controlling cellular proliferation through inducing apoptosis of cancerous cells are also being evaluated. Scientific studies suggest that the hypothetical anti-cancer action of Thymosin Alpha 1 may be mediated through the PI3K/Akt/mTOR signaling pathway. Furthermore, PTEN appears to mediate apoptosis through Thymosin Alpha 1 ^[3]. The specificity of this is yet to be deciphered through further studies.

It is clear from the above-described studies that researchers general assert that Thymosin Alpha 1 appears to exert action through differential molecular and cellular mechanisms that should be investigated in further detail.

Thymosin Alpha 1 Peptide Research

Scientific studies have provided ample data to support its hypothetical consequence within the context of various ailments.

The primary objectives of several ongoing research studies are to evaluate this peptide’s potential individually or in combination with other compounds. Mainly, its action as a sole agent in the research of immune reconstitution disorders, hepatocellular carcinoma, osteoporotic pain, rheumatic heart disease, sepsis, and viral infections, is an active area of scientific investigation. The peptide, in combination with other compounds, is being evaluated for advanced refractory solid tumors, esophageal cancer, rectal carcinoma, malignant melanoma, and non-small cell lung cancer (NSCLC).

Besides prospective well-designed studies, several retrospective evaluations hypothesize the relevance of this peptide in various avenues of scientific research. Particularly in sepsis, organ dysfunction is a major focus. A study compared the benefits of Thymosin Alpha 1 with a placebo. The outcome revealed that Ta1 reduces organ damage among research models of sepsis ^[4].

Another study evaluated the potential of Thymosin Alpha 1 on long-term survival in margin-free (R0)-resected stage IA–IIIA with non-small cell lung cancer (NSCLC) models. Findings suggested that Thymosin Alpha 1 exposure appeared to have improved disease-free survival after R0 resection. The period of the study spanned 24 months ^[5].

The United States Patent Application Publication US 2010/0004174 A1 published in the year 2010 claimed that Thymosin Alpha 1 may exhibit potential benefits in cases of multiple sclerosis, inflammatory bowel disease, Crohn’s disease/ulcerative colitis.

Conclusion

Thymosin Alpha 1 is an endogenous peptide, whose synthetic analog, Thymalfasin, is widely researched as a prospective agent in various ailments. Most prominent theorized actions of Thymosin Alpha 1 are speculated to encompass tumor growth and cancer suppression, boosting immune cell functions, mitigating bacterial, viral, and fungal infections, acting as an anti-inflammatory agent, and augmenting vaccine activity. The most plausible explanation for its diverse potential is that Thymosin Alpha 1 may mediate homeostasis within different organs and systems. However, diverse mechanisms operate to control different diseases. Though a broader profile, this peptide molecular mechanism still needs to be elucidated for each proposed indication.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing.  Bodily introduction of any sort is strictly prohibited by law.  All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References

1. Matteucci C, Nepravishta R, Argaw-Denboba A, Mandaliti W, Giovinazzo A, Petrone V, Balestrieri E, Sinibaldi-Vallebona P, Pica F, Paci M, Garaci E. Thymosin alpha1 interacts with Galectin-1 modulating the beta-galactosides affinity and inducing alteration in the biological activity. Int Immunopharmacol. May 2023;118:110113. doi:10.1016/j.intimp.2023.110113. PMID: 37028279. https://pubmed.ncbi.nlm.nih.gov/37028279/
2. Tao N, Xu X, Ying Y, Hu S, Sun Q, Lv G, Gao J. Thymosin alpha1 and Its Role in Viral Infectious Diseases: The Mechanism and Clinical Application. Molecules. Apr 17 2023;28(8)doi:10.3390/molecules28083539. PMID: 37110771; PMCID: PMC10144173. https://pubmed.ncbi.nlm.nih.gov/37110771/
3. Guo Y, Chang H, Li J, Xu XY, Shen L, Yu ZB, Liu WC. Thymosin alpha 1 suppresses proliferation and induces apoptosis in breast cancer cells through PTEN-mediated inhibition of PI3K/Akt/mTOR signaling pathway. Apoptosis. Aug 2015;20(8):1109-21. doi:10.1007/s10495-015-1138-9. PMID: 26002438. https://pubmed.ncbi.nlm.nih.gov/26002438/
4. Cao M, Wang G, Xie J. Immune dysregulation in sepsis: experiences, lessons and perspectives. Cell Death Discov. Dec 19 2023;9(1):465. doi:10.1038/s41420-023-01766-7. PMID: 38114466; PMCID: PMC10730904. https://pubmed.ncbi.nlm.nih.gov/38114466/
5. Guo CL, Mei JD, Jia YL, Gan FY, Tang YD, Liu CW, Zeng Z, Yang ZY, Deng SY, Sun X, Liu LX. Impact of thymosin alpha1 as an immunomodulatory therapy on long-term survival of non-small cell lung cancer patients after R0 resection: a propensity score-matched analysis. Chin Med J (Engl). Nov 3 2021;134(22):2700-2709. doi:10.1097/CM9.0000000000001819. PMID: 34732663; PMCID: PMC8631386. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8631386/

Tesamorelin, functioning as a synthetic analogue of growth hormone-releasing hormone (GHRH), appears to exhibit a distinctive potential to elicit the production and release of endogenous growth hormone (GH). Empirical investigations indicate a discernible selectivity in activating GH-releasing hormone receptors within the pituitary gland. This selectivity augments its efficacy in manifesting the purported physiological effects.^[1]

In the case of Modified GRF 1-29, this synthetic peptide manifests an extended half-life, likely attributable to its resistance to enzymatic degradation. It has been hypothesized to operate as a robust stimulator of GH secretion, showcasing considerable potential in fostering protein synthesis, facilitating muscle cell growth, and enhancing metabolic processes.^[2]

Finally, Ipamorelin, a synthetic pentapeptide, has been suggested by researchers to operate as a selective agonist for the ghrelin receptor, thereby instigating the release of GH. Its noteworthy potential lies in a high specificity and minimal impact on other hormonal systems, positioning it as a valuable research instrument for precision-targeted GH stimulation.^[3]  This specific attribute renders Ipamorelin an invaluable tool for scientific inquiries directed at understanding and manipulating GH dynamics.

Tesamorelin, Modified GRF and Ipamorelin Blend and Pituitary Gland

The synergy of Tesamorelin, Mod GRF 1-29, and Ipamorelin has been suggested through their substantive interactions with the pituitary gland. These interactions are characterized by precise receptor binding, leading to the modulation of growth hormone (GH) release.

Tesamorelin appears to exhibit an affinity for binding predominantly to growth hormone-releasing hormone (GHRH) receptors located on the surface of somatotrophs in the anterior pituitary gland. Upon this binding, Tesamorelin is speculated to initiate the activation of adenylate cyclase, thereby initiating the production of cyclic adenosine monophosphate (cAMP). This series of molecular events appears to carry the potential to induce the release of growth hormone (GH).^[4] Meanwhile, Modified GRF, apparently engaging with GHRH receptors, emerges as a potential GH secretagogue. Its interaction with GHRH receptors is said to enhance GH release, concomitantly promoting protein synthesis, facilitating muscle cell growth, and amplifying metabolic processes—a phenomenon supported by speculative scientific research.

The structural configuration of the Modified GRF peptide, marked by four amino acid substitutions, appears to enhance its GH-related activity and fortifies its resistance against proteolytic enzymes. These structural modifications are purported to facilitate the covalent binding of “at least 90% of the peptide” to blood albumin, with trace amounts potentially binding to fibrinogen and immunoglobulin G (IgG).

Researchers report “No other chemical species have been found bound to DAC-GRF after [introduction]. This binding extends the half-life of the active pharmacophore, resulting in a markedly prolonged duration of action in several animal species.”^[5]

In contrast, Ipamorelin appears to act as a selective agonist for the ghrelin receptor, which is also expressed on somatotrophs within the pituitary gland. Its binding to ghrelin receptors is posited to induce GH release with high specificity and minimal impact on other hormonal systems. Research findings underscore that Ipamorelin exposure may lead to heightened GH secretion without markedly affecting cortisol, prolactin, or insulin levels, thereby offering a prospect of more targeted and controlled GH stimulation.

Tesamorelin, Mod GRF 1-29 and Ipamorelin Blend and Gastrointestinal Tract

Within the trio of growth hormone-releasing peptides, Tesamorelin has been suggested by researchers to display an apparent capacity to augment gastric emptying and enhance gastrointestinal motility in animal models. Meanwhile, Modified GRF, while exhibiting a minimal impact, appears to contribute to the improvement of gut barrier function and the reduction of intestinal inflammation in animal research models of colitis. Ipamorelin is posited to predominantly interact with the ghrelin receptor within the gastrointestinal (GI) tract.

Following binding to the ghrelin receptors, Ipamorelin may evoke diverse responses, including the promotion of gut motility and the improvement of intestinal absorption. Additionally, Ipamorelin exhibits promise in mitigating inflammation and fostering tissue repair across various models of GI injury. Researchers assert that Ipamorelin may “increase total body fat percentages,” designating the peptide as a “potent and selective stimulator of GH that [may] significantly influence the GI system, body composition, and adiposity.”^[7]

Tesamorelin, Modified GRF and Ipamorelin Blend and Cardiovascular System

Myocardial Infarction (MI) is recognized for inducing scarring in cardiac tissues, potentially compromising heart function, including parameters like ejection fraction.

Animal model studies suggest that growth hormone may expedite the repair of heart tissues post-MI, leading to a reduction in infarct size, enhancement of cardiac ejection fraction, and an overall improvement in cardiac function.^[8]

Researchers observe that, “Through activation of GHS-R1a, secretagogues produced a positive inotropic effect on ischemic cardiomyocytes and protected them from I/R injury, likely by safeguarding or restoring p-PLB (and hence SR Ca2+ content) to facilitate the maintenance or recovery of normal cardiac contractility.”

Research underscores that Tesamorelin, beyond its potential in reducing lipodystrophy, may also contribute to notable reductions in triglyceride levels, total cholesterol levels, and non-HDL-C levels, especially among HIV-positive models.^[9]

Synergistic Potential of Tesamorelin, Mod GRF 1-29 and Ipamorelin Blend

The amalgamation of these peptides is underpinned by the rationale rooted in their distinct mechanisms of action and the potential for synergistically enhanced growth hormone (GH) secretion.

An experimental study elucidated a synergistic augmentation in GH secretion when Tesamorelin and Modified GRF were combined, surpassing the effects observed with either peptide introduced individually. This synergistic hypothesis is attributed to the complementary mechanisms of action and receptor interactions inherent to these peptides.^[6]

Notably, in research models of HIV-associated lipodystrophy, a combination of Tesamorelin and Ipamorelin exhibited more pronounced reductions in visceral adipose tissue compared to Tesamorelin in isolation. However, researchers caution that this effect is transient and reversible upon cessation of exposure.

Scientific research has documented diverse potential actions associated with this peptide blend, encompassing accelerated fat loss, improved sleep quality, mood enhancement, increased energy levels, and potential sustained long-term growth hormone (GH) production, particularly purported with the combined exposure of Ipamorelin and Modified GRF. The protracted elevation of GH production post-cycle may contribute to the enduring maintenance of these benefits over an extended period.

Tesamorelin assumes a pivotal role in enhancing the overall physiological framework of the body. Among the trio of growth hormone-releasing peptides, Tesamorelin is esteemed for its versatility. The concurrent introduction of these three peptides appears to yield a synergistic impact on GH secretion and insulin-like growth factor 1 (IGF-1) levels. This potential synergy may lead to heightened GH secretion, augmented muscle cell growth, improved bone density, cognitive enhancement, cellular repair and regeneration, fat loss, and other multifaceted physiological impacts.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing.  Bodily introduction of any sort is strictly prohibited by law.  All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References

1. National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 9831659, Ipamorelin. https://pubchem.ncbi.nlm.nih.gov/compound/Ipamorelin.
2. National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 56841945. https://pubchem.ncbi.nlm.nih.gov/compound/56841945.
3. National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 16137828, Tesamorelin. https://pubchem.ncbi.nlm.nih.gov/compound/Tesamorelin.
4. Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-. Tesamorelin. [Updated 2018 Oct 20]. https://www.ncbi.nlm.nih.gov/books/NBK548730/
5. Sam L. Teichman and others, 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, The Journal of Clinical Endocrinology & Metabolism, Volume 91, Issue 3, 1 March 2006, Pages 799–805, https://doi.org/10.1210/jc.2005-1536 ; https://academic.oup.com/jcem/article/91/3/799/2843281
6. Bedimo R. Growth hormone and tesamorelin in the management of HIV-associated lipodystrophy. HIV AIDS (Auckl). 2011;3:69-79. doi: 10.2147/HIV.S14561. Epub 2011 Jul 10. PMID: 22096409; PMCID: PMC3218714. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3218714/
7. Sinha DK, Balasubramanian A, Tatem AJ, Rivera-Mirabal J, Yu J, Kovac J, Pastuszak AW, Lipshultz LI. Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Transl Androl Urol. 2020 Mar;9(Suppl 2):S149-S159. doi: 10.21037/tau.2019.11.30. PMID: 32257855; PMCID: PMC7108996 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108996/
8. Ma Y, Zhang L, Edwards JN, Launikonis BS, Chen C. Growth hormone secretagogues protect mouse cardiomyocytes from in vitro ischemia/reperfusion injury through regulation of intracellular calcium. PLoS One. 2012;7(4):e35265. https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0035265 Epub 2012 Apr 6. PMID: 22493744; PMCID: PMC3320867.
9. Stanley TL, Falutz J, Marsolais C, Morin J, Soulban G, Mamputu JC, Assaad H, Turner R, Grinspoon SK. Reduction in visceral adiposity is associated with an improved metabolic profile in HIV-infected patients receiving tesamorelin. Clin Infect Dis. 2012 Jun;54(11):1642-51. doi: 10.1093/cid/cis251. Epub 2012 Apr 10. PMID: 22495074; PMCID: PMC3348954. https://pubmed.ncbi.nlm.nih.gov/22495074/

Protein and Peptide Structural Elucidation

The H2-relaxin protein, a complex ensemble comprising relaxin, H3-relaxin, insulin-like peptide-3, and insulin-like peptide-5, is considered by scientists to govern diverse biological impacts, extending its influence to gene regulation and reproductive, musculoskeletal, and cardiovascular systems. This protein family appears to intricately interact with four distinct receptors – RXFP-1, RXFP-2, RXFP-3, and RXFP-4 – each wielding specific physiological actions.

RXFP-1, for instance, is considered to modulate sperm motility, joint function, and may play a role in pregnancy. RXFP-2 appears to influence testicular descent, RXFP-3 is implicated in sleep regulation, and RXFP-4 exhibits indications of involvement in hunger cycles. Given the expansive array of receptor interactions and the consequential biological impacts, intensive investigations have been undertaken, delving into the H2-relaxin protein and its derivatives, including the intriguing B7-33 peptide, to unveil their manifold research implications.

B7-33 Peptide Synthesis and Structural Modification

The conventional relaxin peptide encompasses four distinct components: a signal peptide, a B chain, a C chain, and a COOH terminal. Initial attempts to replicate this intricate structure resulted in high insolubility and inactivity in peptides. However, through meticulous structural modifications involving the production of a B chain and elongation of the COOH terminal, scientists achieved a groundbreaking milestone in 2016 – synthesizing the first-ever soluble analog, B7-33 peptide.^[3]

B7-33 and Activation of pERK Pathway

Current research suggests that the B7-33 peptide may diverge from the canonical cAMP pathway typically associated with the anti-fibrotic properties of H2-relaxin. Activation of the cAMP pathway by H2-relaxin is considered to stimulate tumorigenesis, an adverse action of relaxin exposure. Intriguingly, the B7-33 peptide appears to display a notable affinity for RXFP-1 receptors. Binding the peptide to these receptors may induce pERK pathway activation, potentially resulting in heightened synthesis of matrix metalloproteinase 2 (MMP-2). The pivotal role of MMP-2 lies in inhibiting tissue scarring, thus providing a promising avenue for fibrosis research.^[2]

Research and Scientific Studies

B7-33 Peptide and Preeclampsia

Preeclampsia is characterized by maternal hypertension and fetal growth restriction. A pivotal study delved into the impact of B7-33 peptide exposure on research models of preeclampsia using cytotrophoblasts. The results indicated an elevation in vascular endothelial growth factor (VEGF) levels, indicating the potential of B7-33 to counteract elevated glucose and marinobufagenin (MBG) levels, thereby attenuating the pathophysiology of preeclampsia.^[4]

As per researchers Syeda H Afroze et al: ”Both B7-33 and its lipidated derivative mitigate the MBG- and hyperglycemia-induced dysfunction of CTBs by attenuating anti-angiogenic phenotype similar to that seen in preE. Moreover, the B7-33 and its lipidated derivative-induced effect on CTBs are attenuated by a relaxin antagonist.”^[4]

B7-33 Peptide and Vasoprotection

H2-relaxin has earned its reputation as a vasoprotective compound among researchers, as a potential mitigator of cardiac failure and fibrosis. However, the cumbersome and expensive exogenous production of H2-relaxin prompted investigations into its analog, B7-33 peptide. In a comprehensive study involving male Wistar rats, vascular functions were meticulously assessed after the introduction of a placebo peptide, H2-relaxin, or B7-33 peptide. While impacts in the renal artery and abdominal aorta were negligible, both B7-33 and H2-relaxin appeared to have exhibited improvements in vasodilatory properties in the mesenteric artery. Another study in female mice hinted at potential effectiveness in preventing endothelial dysfunction induced by placental trophoblast conditioned media.^[5]

Sarah A. Marshall et al. state, “In conclusion, … B7-33 replicated the acute beneficial vascular effects of serelaxin in rat mesenteric arteries and also prevented endothelial dysfunction induced by placental trophoblast conditioned media in mouse mesenteric arteries.”^[5]

B7-33 Peptide and Anti-Fibrosis

Studies have posited that fully extended H2-relaxin may inadvertently stimulate carcinogenic cell proliferation via cAMP activation. In stark contrast, introduction of the B7-33 peptide to mice models of myocardial infarction indicated a substantial reduction in cardiac tissue fibrosis and improved heart function. This remarkable result was attributed to an increased concentration of matrix metalloproteinase protein, countering collagen-damaging cells and preventing fibrosis. Furthermore, in a prostate cancer study, both low and high concentrations of B7-33 appeared to have supported the prevention of fibrosis development and tumor spread. This finding suggested the exclusive activation of the pERK pathway, thereby possibly preventing cancer cell spread without activating cAMP. ^[6,7]

B7-33 Peptide as Coating Material

To surmount the immune response against foreign substances, a potential solution involves coating internal devices with the B7-33 peptide. A meticulous study in mice involved the implantation of a device coated with the peptide, which was released to counteract the fibrotic effects on the research models. The results indicated a significant reduction in device thickness induced by fibrosis over the 6-week duration of the study. While this marks only the initial step, these findings strongly suggest the potential of B7-33 peptide within the realm of coating material for devices and implants, though further research is ongoing.

In Summary

B7-33 peptide, a structural variant of H2-relaxin, emerges as a promising research compound with distinctive potential action. Its proposed action to activate the pERK pathway without inducing cAMP makes it a unique candidate in the realm of anti-fibrotic and vasoprotective research. The notable anti-fibrotic and vasoprotective potential of B7-33 signify its possible relevance in research related diverse cardiovascular and pulmonary disorders and preeclampsia.

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing.  Bodily introduction of any sort is strictly prohibited by law.  All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References:

1. Summers RJ. Recent progress in the understanding of relaxin family peptides and their receptors. Br J Pharmacol. 2017 May;174(10):915-920. doi: 10.1111/bph.13778. PMID: 28447360. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5406287/
2. Mohammed Akhter Hossain et al., A single-chain derivative of the relaxin hormone is a functionally selective agonist of the G protein-coupled receptor, RXFP1, Drug Discovery Biology Pharmacology Monash Biomedicine Discovery Institute, Vol 7, 2016.
3. Nitin A Patil et al, Relaxin family peptides: structure–activity relationship studies, British Pharmacological Society, vol 174 issue 10, published 06 December 2016. https://doi.org/10.1111/bph.13684
4. H Afroze et al., Abstract P3042: Novel Peptide B7-33 and Its Lipidated Derivative Protect Cytotrophoblasts From Preeclampsia Phenotype in a Cellular Model of the Syndrome, 4 Sep 2019. https://doi.org/10.1161/hyp.74.suppl_1.P3042
5. Marshall SA, O’Sullivan K, Ng HH, Bathgate RAD, Parry LJ, Hossain MA, Leo CH. B7-33 replicates the vasoprotective functions of human relaxin-2 (serelaxin). Eur J Pharmacol. 2017 Jul 15;807:190-197. doi: 10.1016/j.ejphar.2017.05.005. Epub 2017 May 3. PMID: 28478069. https://pubmed.ncbi.nlm.nih.gov/28478069/
6. Silvertown JD, Ng J, Sato T, Summerlee AJ, Medin JA. H2 relaxin overexpression increases in vivo prostate xenograft tumor growth and angiogenesis. Int J Cancer. 2006 Jan 1;118(1):62-73. https://pubmed.ncbi.nlm.nih.gov/16049981
7. Shu Feng, Irina U. Agoulnik, Natalia V. Bogatcheva, Aparna A. Kamat, Bernard Kwabi-Addo, Rile Li, Gustavo Ayala, Michael M. Ittmann and Alexander I. Agoulnik, Relaxin Promotes Prostate Cancer Progression, March 2007. https://clincancerres.aacrjournals.org/content/13/6/1695

CJC-1295 represents a molecular entity that appears to exhibit a binding affinity for the growth hormone-releasing hormone (GHRH) receptors, thereby potentially instigating the secretion of growth hormone by pituitary cells. Originating from GHRH 1-29, CJC-1295 encompasses the functional sequence composed of the initial 29 amino acids of GHRH. This peptide has been subject to tetra substitution and modification via the integration of a drug affinity complex (DAC) element. The DAC component binds to plasma proteins, apparently augmenting the pharmacokinetic properties of CJC-1295.^[1]

Growth Hormone Releasing Peptide 2 (GHRP-2) represents a synthetic hexapeptide comprising of six amino acids. Studies suggest that this peptide binds to the ghrelin or growth hormone secretagogues 1a receptors (GHS-R1a), which are present within the hypothalamus and the pituitary gland. Consequently, GHRP-2 appears to stimulate the production of growth hormones in pituitary cells expressing the GHS-R1a receptor.^[2]

By activating distinct receptors via separate biochemical pathways, these peptides are hypothesized to synergistically elevate GH release from the anterior pituitary, potentially surpassing the individual capacities of each peptide.

GHRP-2 and CJC 1295 Peptide Blend

Both GHRP-2 and CJC-1295 have undergone extensive evaluation in diverse animal models, and are speculated to yield favorable outcomes in terms of muscle hypertrophy and hyperplasia, cardiac function, and modulation of the immune system.

Furthermore, both peptides appear to exhibit the potential to reduce blood sugar levels while promoting the accrual of lean body mass at the expense of fat deposition. Notably, these peptides are recognized for their capacity to possibly induce fat loss through the amplification of metabolic processes. 

This probable reduction in adipose tissue has been correlated with enhanced insulin sensitivity and notable advancements in cases of type 2 diabetes.

Research and Scientific Studies

Effect of GHRP-2 and CJC-1295 Blend on Growth Hormone Secretion

Scientific investigations suggest that GHRP-2 peptide appears to display considerable affinity towards the growth hormone secretagogues 1a receptor (GHS-R1a) located within the hypothalamus and the pituitary gland. In contrast, CJC-1295 appears to engage with the growth hormone-releasing hormone receptor (GHRH-R), specifically in the pituitary gland. 

Research suggests that this amalgamated peptide blend may elevate plasma growth hormone (GH) levels, implying their potential to augment GH release. Moreover, sustained release dynamics of this blend appear to prolong the half-life of the peptides, possibly leading to the extension of GH secretion compared to the individual administration of peptides. 

Studies have reported “basal GH levels may increase by 7.5-fold” contributing to an “overall 46% increase in GH secretion.”^[3]

This phenomenon seems to regulate the pulsatile release of growth hormones, subject to negative feedback mechanisms, thereby potentially averting the development of supratherapeutic GH levels and their associated complications.^[4]

Effect of GHRP-2 and CJC-1295 Blend on Fat Metabolism

Through distinct mechanisms, GHRP-2 and CJC-1295 peptides appear to stimulate GH release from pituitary cells, thereby facilitating fat loss. Scientific exploration indicates that CJC-1295 may exhibit a prolonged half-life compared to endogenous GHRH. 

Growth hormone is considered to demonstrate anti-obesity effects through various mechanisms, including the promotion of lipolysis, enhanced utilization of fatty acids as an energy source, and heightened fat oxidation. The peptide blend, through growth hormone release, has reportedly exhibited increased glucose synthesis and decreased glucose uptake, resulting in heightened fat utilization and storage. Studies suggest that ghrelin-like peptides such as GHRP-2 may serve as a crucial hormonal signal of nutritional status to the somatotropic axis, playing a pivotal role in integrating energy balance with the growth process.^[5]

Effect of GHRP-2 and CJC-1295 Blend on Osteoporosis

A clinical study conducted on eighty postmenopausal research models of osteoporosis undergoing estrogen therapy reported significant findings regarding the effects of growth hormone (GH) peptide (such as GHRP-2 and CJC 1295) on bone health. 

The research subjects were randomized into groups receiving one of two concentrates of growth hormone or a placebo for 18 months in a double-blinded setup. The results indicated that the total body bone mineral content was notably higher in the higher concentration GH group at the 18-month mark. Over the course of 3 years, the experimental GH groups exhibited increases in total body and femoral neck bone mineral content. At the 4-year follow-up, the higher concentration GH group demonstrated a remarkable 14% increase in lumbar spine bone mineral content compared to the placebo. 

Although no disparities in bone mineral density or content were observed between groups at the 5-year follow-up, the study suggests “GH (peptides) could be used as an anabolic agent in osteoporosis”^[6], especially when combined with hormone replacement therapy and calcium/vitamin D supplementation.

Effect of GHRP-2 and CJC-1295 Blend on Immune System

Recent research underscores the intricate interplay between the neuroendocrine system and immune functions, illuminating a complex bidirectional relationship. 

Notably, multiple lymphoid organs, including the thymus, spleen, and peripheral blood, have been identified as sites of growth hormone (GH) production, with the GH receptor expressed across various subpopulations of lymphocytes. 

In vitro and animal studies indicate the possible role of GH in immunoregulation. GH peptides appear to stimulate the proliferation of T and B cells, facilitating immunoglobulin synthesis and promoting the maturation of myeloid progenitor cells. Moreover, GH also appears to modulate cytokine responses, thereby possibly influencing the intricate network of immune signaling.^[7]

Interestingly, while GH deficiency (GHD) typically does not manifest as immunodeficiency, minor aberrations in immune function have been documented, albeit significantly less pronounced than those observed in animal models of GHD. This observation suggests the plausibility of local GH production within the immune system compensating for the absence of systemic GH. 

Disclaimer: The products mentioned are not intended for human or animal consumption. Research chemicals are intended solely for laboratory experimentation and/or in-vitro testing.  Bodily introduction of any sort is strictly prohibited by law.  All purchases are limited to licensed researchers and/or qualified professionals. All information shared in this article is for educational purposes only.

References:

1. Ionescu M, Frohman LA. Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog. J Clin Endocrinol Metab. 2006 Dec;91(12):4792-7. doi: 10.1210/jc.2006-1702. Epub 2006 Oct 3. PMID: 17018654. https://pubmed.ncbi.nlm.nih.gov/17018654/ 
2. Yamamoto D, Ikeshita N, Matsubara T, Tasaki H, Herningtyas EH, Toda K, Iida K, Takahashi Y, Kaji H, Chihara K, Okimura Y. GHRP-2, a GHS-R agonist, directly acts on myocytes to attenuate the dexamethasone-induced expressions of muscle-specific ubiquitin ligases, Atrogin-1 and MuRF1. Life Sci. 2008 Feb 27;82(9-10):460-6. doi: 10.1016/j.lfs.2007.11.019. Epub 2007 Dec 5. PMID: 18191156. https://pubmed.ncbi.nlm.nih.gov/18191156/ 
3. Ionescu M, Frohman LA. Pulsatile secretion of growth hormone (GH) persists during continuous stimulation by CJC-1295, a long-acting GH-releasing hormone analog. J Clin Endocrinol Metab. 2006 Dec;91(12):4792-7. doi: 10.1210/jc.2006-1702. Epub 2006 Oct 3. PMID: 17018654. https://pubmed.ncbi.nlm.nih.gov/17018654/ 
4. Sigalos JT, Pastuszak AW. The Safety and Efficacy of Growth Hormone Secretagogues. Sex Med Rev. 2018 Jan;6(1):45-53. doi: 10.1016/j.sxmr.2017.02.004. Epub 2017 Apr 8. PMID: 28400207; PMCID: PMC5632578. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5632578/ 
5. Laferrère B, Hart AB, Bowers CY. Obese subjects respond to the stimulatory effect of the ghrelin agonist growth hormone-releasing peptide-2 on food intake. Obesity (Silver Spring). 2006 Jun;14(6):1056-63. doi: 10.1038/oby.2006.121. PMID: 16861611; PMCID: PMC2824649. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2824649/
6. Landin-Wilhelmsen K, Nilsson A, Bosaeus I, Bengtsson BA. Growth hormone increases bone mineral content in postmenopausal osteoporosis: a randomized placebo-controlled trial. J Bone Miner Res. 2003 Mar;18(3):393-405. doi: 10.1359/jbmr.2003.18.3.393. PMID: 12619921. https://pubmed.ncbi.nlm.nih.gov/12619921/ 
7. Meazza C, Pagani S, Travaglino P, Bozzola M. Effect of growth hormone (GH) on the immune system. Pediatr Endocrinol Rev. 2004 Aug;1 Suppl 3:490-5. PMID: 16444180. https://pubmed.ncbi.nlm.nih.gov/16444180/