Ipamorelin

Potential Benefits of Ipamorelin

• Builds lean muscle mass [1-28]
• Maintains healthy bones [29-36]
• Improves digestive health [37-46]
• Maintains a healthy heart [47-61]
• Improves blood sugar levels [62-72]
• Strengthens the immune system [73-111]
• Prevents cognitive decline [112-148]
• Improves sex drive and sexual function [149-183]
• Enhances tissue regeneration [182-203]
• Improves sleep quality [204-224]

What is Ipamorelin?

Ipamorelin is considered a growth hormone releasing peptide (GHRP) or growth hormone secretagogue. As a pentapeptide (composed of five amino acids), it has the capacity to mimic the body’s natural release of growth hormone and ghrelin (the hunger hormone). Because this peptide does not affect the release of other hormones in the body such as acetylcholine, aldosterone, cortisol, and prolactin, it has virtually no negative side effects. Therefore, it is considered one of the safest and most effective forms of growth hormone replacement therapy, widely used to fight the effects of aging, manage certain diseases, enhance sports performance, and balance growth hormone deficiency. Furthermore, most medical professionals prescribe ipamorelin more than other therapies because it can help optimize human growth hormone for a longer period of time, thus having a more potent effect.

How Ipamorelin Works?

After ipamorelin injection, a selective pulse is sent to the pituitary gland, which in turn releases growth hormone within the body. This causes cells to move toward the muscles to support growth and development while preventing any bone or cartilage deformities. In addition, ipamorelin increases cell synthesis, insulin levels, and ghrelin levels. All of these vital functions work to promote fat loss and increase muscle mass and strength.

Chemical Structure of Ipamorelin

Research on Ipamorelin

Builds Lean Muscle Mass

Getting a higher percentage of lean muscle mass while reducing body fat is the most pronounced reason why bodybuilders, athletes, and even amateurs opt for ipamorelin injections. Studies show that ipamorelin has potent muscle-building properties that can help those who want to improve their body composition:

1. Studies show that ipamorelin boosts the levels of growth hormone (GH), a process that is vital in muscle growth and development. [1-8]
2. By increasing GH levels, ipamorelin helps enhance muscle synthesis. [1-17]
3. As a growth hormone releasing peptide, ipamorelin promotes muscle growth and inhibits muscle wasting. [18-19]
4. In a severely emaciated anorexia nervosa patient, one-year intranasal application of growth hormone-releasing peptide improved muscle mass and strength. [20]
5. By increasing ghrelin levels, ipamorelin improves muscle mass by increasing food intake. [21-23]
6. Growth hormone-releasing peptide administration increases muscle mass by promoting muscle regeneration and increasing the levels of collagen. [24-27]
7. In rats, ipamorelin administration counteracted muscle wasting induced by glucocorticoid injections. [28]

Maintains Healthy Bones

Aside from achieving lean muscle mass, ipamorelin administration can also help maintain a healthy skeletal frame and prevent various bone disorders. Studies assessing the beneficial effects of ipamorelin on bone health have shown positive results:

1. In GH-deficient children, administration of growth hormone-releasing peptides such as ipamorelin increased bone growth velocity. [29-33]
2. In rats, ipamorelin administration induced longitudinal bone growth. [34]
3. In adult female rats, ipamorelin administration increased bone mineral content without any side effects or toxicities. [35]
4. A study reported that ipamorelin’s ability to stimulate the release of growth hormone can help in bone formation and growth. [36]

Improves Digestive Health

Ipamorelin also plays an integral role in maintaining digestive system health. Studies show that growth hormone-releasing peptides such as ipamorelin help improve gastrointestinal function:

1. Growth hormone-releasing peptide improves digestive health by protecting against various types of ulcers. [37]
2. In humans, ipamorelin administration improves gastric motility (contractions of gastric smooth muscle) by increasing the levels of ghrelin. [38]
3. In a severely emaciated anorexia nervosa patient, one-year intranasal application of growth hormone-releasing peptide improved digestive tract dysfunction as evidenced by an increase in food intake and body weight. [39]
4. In patients who had undergone major abdominal surgery, ipamorelin administration improved upper and lower gastrointestinal tract function. [40]
5. In rats, ipamorelin administration boosted ghrelin levels, which in turn improved gastrointestinal function. [41-43]
6. In a rodent model of postoperative ileus (malfunctioning of intestinal motility after abdominal surgery), ipamorelin administration accelerated gastric emptying, which is suggestive of improved gastrointestinal function. [44-45]
7. In rats, ipamorelin administration increased fecal pellet output following abdominal surgery. [46]

Maintains a Healthy Heart

Recent human clinical trials and animal studies show that ipamorelin and other growth hormone- releasing peptides have cardioprotective effects that can help combat various heart diseases:

1. In patients with heart disease, the administration of growth hormone-releasing peptide improved cardiac output and ventricular mechanical work. [47]
2. In patients with coronary artery disease undergoing bypass surgery, the administration of growth hormone-releasing peptide increased left ventricular ejection fraction. [48]
3. In human subjects, the administration of growth hormone-releasing peptide helped protect against heart damage induced by lack of oxygen. [49]
4. In healthy volunteers, acute intravenous administration of growth hormone-releasing peptide induced a clear and prompt increase in left ventricular ejection fraction. [50-51]
5. In patients with heart failure, ipamorelin administration increased heart muscle contractions by boosting the levels of IGF-1. [52-54]
6. In rats, the administration of growth hormone releasing peptide protected against heart injury caused by lack of oxygen. [55]
7. In rats subjected to experimental myocardial infarction, the administration of growth hormone releasing peptide increased blood volume pumped by the left ventricle of the heart. [56]
8. In rats, growth hormone-releasing peptide administration increased the strength of muscular contractions of the heart. [57]
9. In rats, growth hormone-releasing peptide administration prevented heart failure by protecting against radical damage. [58]
10. In hamsters with dilated cardiomyopathy, 4-week treatment with growth hormone releasing peptide attenuated left ventricular dysfunction and dilation. [59]
11. In dogs with decreased blood supply to the heart, growth hormone releasing peptide administration prevented death by increasing heart wall thickness, which is suggestive of improved blood circulation. [60]
12. In pigs, growth hormone releasing peptide administration exhibited antioxidant effects, which in turn reduced damage to the heart muscle. [61]

Improves Blood Sugar Levels

Ipamorelin also has potent blood sugar-lowering effects which can help prevent diabetes and other fatal medical conditions associated with chronic elevation of blood sugar levels. Strong scientific evidence supports this beneficial effect:

1. In diabetic patients, the administration of growth hormone-releasing peptide improved blood sugar levels by increasing GH secretion. [62]
2. By boosting GH levels, ipamorelin can help lower one’s risk of diabetes. [63]
3. In diabetic rats, ipamorelin administration stimulated the release of insulin, a hormone that lowers blood sugar levels. [64-65]
4. In diabetic rats, ipamorelin administration lowered blood sugar levels by increasing IGF-1 production. [66]
5. The intravenous injection of human growth hormone releasing peptide in rats increased the blood levels of insulin. [67]
6. In diabetic rats, pretreatment with synthetic growth hormone releasing peptide improved insulin secretion and insulin reserves. [68-72]

Strengthens the Immune System

There is increasing evidence that ipamorelin may help boost immune function through various important mechanisms:

1. The administration of growth hormone releasing peptides may help improve the quality of life of cancer patients by correcting nutritional and metabolic states. [73]
2. In patients with growth hormone deficiency, boosting GH levels through growth hormone releasing peptide administration increased the levels of white blood cells, T cells, and B cells of the immune system. [74-75]
3. In rats, the administration of growth hormone-releasing peptides such as ipamorelin countered inflammation via the AKT1-activated pathway and reduced programmed cell death (apoptosis) while combating oxidative stress. [76-77]
4. In animal models, growth hormone releasing peptide administration protected against multiple sclerosis, nerve damage, and brain diseases. [78-81]
5. In mice, growth hormone releasing peptide administration enhanced antibody titers against various harmful microorganisms. [82]
6. As a growth hormone releasing peptide, ipamorelin helps strengthen the immune system by boosting GH levels. [83-95]
7. As a growth hormone stimulant, ipamorelin enhances immune function by stimulating T and B cell proliferation and immunoglobulin synthesis and aiding in the maturation of stem cells and modulation of the inflammatory response. [96]
8. By increasing GH levels, ipamorelin improves the functional activity of circulating phagocyte cells (cells that engulf foreign bodies). [97]
9. Ipamorelin can also improve the cytotoxic activity mediated by natural killer cells. [98-100]
10. By boosting GH levels, ipamorelin can increase the production of various immune system cells such as IL-1β, TNF-α, IL-6, and cytokines. [101-102]
11. Growth hormone secretagogues such as ipamorelin enhance the development of the thymus, a gland that produces T cells for the immune system. [103-110]
12. The administration of growth hormone secretagogues increased tumor resistance in mice. [111]

Prevents Cognitive Decline

By restoring growth hormone to healthy levels, ipamorelin together with other growth hormone- releasing peptides can help prevent age-related decline in cognitive function as well as those caused by certain medical conditions:

1. In patients with cognitive impairment, the administration of growth hormone secretagogues such as ipamorelin improved age-related decline in cognitive function. [112]
2. In older adults, the administration of growth hormone secretagogues improved short-term memory and active problem-solving skills. [113]
3. In healthy older men and women, the administration of growth hormone secretagogues improved cognitive function. [114]
4. In healthy older adults, the administration of growth hormone secretagogues prevented cognitive decline associated with aging and Alzheimer’s disease. [115]
5. In adults with mild cognitive impairment and older adults with normal cognitive function, the administration of growth hormone secretagogues improved cognitive function by increasing the levels of brain chemicals such as gamma-Aminobutyric acid and N-acetyl-aspartyl-glutamate. [116]
6. By boosting ghrelin levels, ipamorelin helps protect brain cells against programmed cell death, thereby preventing cognitive decline. [117-122]
7. Ipamorelin administration can help prevent Parkinson’s disease by boosting ghrelin levels, which in turn prevents the loss of dopamine, a brain chemical that plays a major role in reward-motivated behavior. [123-130]
8. The administration of growth hormone secretagogues boosts IGF-1 levels, which in turn activates intracellular pathways involved in the protection of nerve cells in the brain. [131-148]

Improves Sex Drive and Sexual Function

As a growth hormone releasing peptide, ipamorelin can indirectly increase libido and improve sexual function by boosting the levels of GH and IGF-1:

1. Compelling evidence suggests that growth hormone deficiency is strongly linked with low libido and erectile dysfunction, suggesting that boosting GH levels through ipamorelin supplementation may have beneficial effects on libido. [149-156]
2. There is increasing evidence that IGF-1 deficiency is strongly linked with low libido and erectile dysfunction, suggesting that ipamorelin supplementation may help improve sexual drive and function. [157-163]
3. In age-advanced men, growth hormone releasing peptide supplementation significantly improved libido and general well-being. [164]
4. By increasing GH and IGF-1 levels, ipamorelin indirectly improves sexual function by increasing the levels of nitric oxide, a molecule naturally produced in the body that stimulates harder and longer penile erections. [165-173]
5. Aside from GH and IGF-1 levels, ipamorelin administration also boosts testosterone and estrogen levels, which are necessary for the regulation of sexual thoughts, desire, and sexual function. [174-175]
6. Studies show that growth hormone-releasing peptides play an integral role in penile erection and sexual arousal. [176-183]

Enhances Tissue Regeneration

Growth hormone-releasing peptides such as ipamorelin can help repair damaged tissues caused by a sports injury or physical trauma. There is strong scientific evidence supporting the regenerative properties of ipamorelin:

1. Ipamorelin and other peptides can be a therapeutic option for cartilage repair and regeneration. [184-185]
2. Peptides can enhance tissue regeneration by improving collagen synthesis and providing structural and biochemical support to the surrounding cells of the injured area. [186]
3. Peptides can also speed up the wound healing process by increasing the production of collagen. [187-189]
4. Peptides can accelerate the healing of various cartilage defects. [190-193]
5. By recruiting certain cells needed for the repair of damaged tissue, peptides reduce healing time and improve tissue recovery. [194-195]
6. Peptides have the ability to support the structure of damaged tissues while allowing them to heal. [196]
7. Peptides enhance tissue regeneration by promoting chondrogenesis, the process by which cartilage is developed. [197-200]
8. By promoting cell adhesion, ipamorelin and other peptides can enhance cartilage tissue repair. [201-203]

Improves Sleep Quality

Ipamorelin and other growth hormone-releasing peptides play an integral role in promoting restful sleep. Studies show that by increasing GH and IGF-1 levels, as well as enhancing certain sleep processes, ipamorelin significantly improves sleep quality and quantity:

1. In normal men, the administration of growth hormone-releasing peptide increased slow-wave sleep (SWS), which is often referred to as deep sleep. [204]
2. In young healthy men, intravenous injections of growth hormone-releasing peptides during sleep consistently stimulated slow-wave sleep. [205]
3. In normal young males, the administration of growth hormone releasing peptide increased stage 2 sleep. [206]
4. By increasing GH levels, ipamorelin significantly improves the deep sleep stage. [207-212]
5. By increasing IGF-1 levels, ipamorelin promotes deep sleep. [213-223]
6. In rats, growth hormone releasing peptide administration activated sleep regulatory neurons in the brain. [224]

Associated Side Effects of Ipamorelin

Ipamorelin side effects are very uncommon. There have been some side effects associated with the use of this drug wherein the patient had one of the issues listed below at some point while being on ipamorelin. However, these side effects weren’t confirmed to be associated with the treatment and could have been a coincidence and not related to the use of ipamorelin. Despite this, it was listed as a side effect associated with ipamorelin even though these associated side effects are very uncommon.

Side effects associated with ipamorelin may include the following:

• Changes in taste
• Chest tightness
• Difficulty swallowing
• Drowsiness
• Dry mouth
• Flushing of the skin
• Headache
• Hives
• Hyperactivity
• Increased hunger
• Nausea
• Vomiting

References

1. Raun K, Hansen BS, Johansen NL, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998;139(5):552-61.
2. Jiménez-reina L, Cañete R, De la torre MJ, Bernal G. Influence of chronic treatment with the growth hormone secretagogue Ipamorelin, in young female rats: somatotroph response in vitro. Histol Histopathol. 2002;17(3):707-14.
3. Gobburu JV, Agersø H, Jusko WJ, Ynddal L. Pharmacokinetic-pharmacodynamic modeling of ipamorelin, a growth hormone releasing peptide, in human volunteers. Pharm Res. 1999;16(9):1412-6.
4. Thomas A, Delahaut P, Krug O, Schänzer W, Thevis M. Metabolism of growth hormone releasing peptides. Anal Chem. 2012;84(23):10252-9.
5. Johansen PB, Hansen KT, Andersen JV, Johansen NL. Pharmacokinetic evaluation of ipamorelin and other peptidyl growth hormone secretagogues with emphasis on nasal absorption. Xenobiotica. 1998;28(11):1083-92.
6. Semenistaya E, Zvereva I, Thomas A, Thevis M, Krotov G, Rodchenkov G. Determination of growth hormone releasing peptides metabolites in human urine after nasal administration of GHRP-1, GHRP-2, GHRP-6, Hexarelin, and Ipamorelin. Drug Test Anal. 2015;7(10):919-25.
7. Semenistaya E, Zvereva I, Thomas A, Thevis M, Krotov G, Rodchenkov G. Determination of growth hormone releasing peptides metabolites in human urine after nasal administration of GHRP-1, GHRP-2, GHRP-6, Hexarelin, and Ipamorelin. Drug Test Anal. 2015;7(10):919-25.
8. Hansen TK, Ankersen M, Raun K, Hansen BS. Highly potent growth hormone secretagogues: hybrids of NN703 and ipamorelin. Bioorg Med Chem Lett. 2001 Jul 23;11(14):1915-8.
9. Velloso CP. Regulation of muscle mass by growth hormone and IGF-I. British Journal of Pharmacology. 2008;154(3):557-568. doi:10.1038/bjp.2008.153.
10. Tavares ABW, Micmacher E, Biesek S, et al. Effects of Growth Hormone Administration on Muscle Strength in Men over 50 Years Old. International Journal of Endocrinology. 2013;2013:942030. doi:10.1155/2013/942030.
11. Devesa J, Almengló C, Devesa P. Multiple Effects of Growth Hormone in the Body: Is it Really the Hormone for Growth? Clinical Medicine Insights Endocrinology and Diabetes. 2016;9:47-71. doi:10.4137/CMED.S38201.
12. Taaffe DR, Pruitt L, Reim J, et al. Effect of recombinant human growth hormone on the muscle strength response to resistance exercise in elderly men. J Clin Endocrinol Metab. 1994;79(5):1361-6.
13. Weber MM. Effects of growth hormone on skeletal muscle. Horm Res. 2002;58 Suppl 3:43-8.
14. Welle S, Thornton C, Statt M, Mchenry B. Growth hormone increases muscle mass and strength but does not rejuvenate myofibrillar protein synthesis in healthy subjects over 60 years old. J Clin Endocrinol Metab. 1996;81(9):3239-43.
15. Sotiropoulos A, Ohanna M, Kedzia C, et al. Growth hormone promotes skeletal muscle cell fusion independent of insulin-like growth factor 1 up-regulation. Proceedings of the National Academy of Sciences of the United States of America. 2006;103(19):7315-7320. doi:10.1073/pnas.0510033103.
16. Gonzalez S, Sathyapalan T, Javed Z, Atkin SL. Effects of Growth Hormone Replacement on Peripheral Muscle and Exercise Capacity in Severe Growth Hormone Deficiency. Front Endocrinol (Lausanne). 2018;9:56.
17. Peroni CN, Hayashida CY, Nascimento N, et al. Growth hormone response to growth hormone-releasing peptide-2 in growth hormone-deficient Little mice. Clinics. 2012;67(3):265-272. doi:10.6061/clinics/2012(03)11.
18. Berlanga-Acosta J, Abreu-Cruz A, Barco Herrera DG, et al. Synthetic Growth Hormone-Releasing Peptides (GHRPs): A Historical Appraisal of the Evidences Supporting Their Cytoprotective Effects. Clinical Medicine Insights Cardiology. 2017;11:1179546817694558. doi:10.1177/1179546817694558.
19. Lim CJ, Jeon JE, Jeong SK, et al. Growth hormone-releasing peptide-biotin conjugate stimulates myocytes differentiation through insulin-like growth factor-1 and collagen type I. BMB Reports. 2015;48(9):501-506. doi:10.5483/BMBRep.2015.48.9.258.
20. Haruta I, Fuku Y, Kinoshita K, et al. One-year intranasal application of growth hormone releasing peptide-2 improves body weight and hypoglycemia in a severely emaciated anorexia nervosa patient. Journal of Cachexia, Sarcopenia and Muscle. 2015;6(3):237-241. doi:10.1002/jcsm.12028.
21. Inui A. Ghrelin: an orexigenic and somatotrophic signal from the stomach. Nat Rev Neurosci. 2001;2:551–560.
22. Chen CY, Asakawa A, Fujimiya M, Lee SD, Inui A. Ghrelin gene products and the regulation of food intake and gut motility. Pharmacol Rev. 2009;61:430–481.
23. Laferrère B, Abraham C, Russell CD, Bowers CY. Growth Hormone Releasing Peptide -2 (GHRP-2), like ghrelin, increases food intake in healthy men. The Journal of clinical endocrinology and metabolism. 2005;90(2):611-614. doi:10.1210/jc.2004-1719.
24. Zhou S, Salisbury J, Preedy VR, Emery PW. Increased collagen synthesis rate during wound healing in muscle. PLoS One. (2013);8:e58324. doi: 10.1371/journal.pone.0058324.
25. Bonaldo P, Braghetta P, Zanetti M, Piccolo S, Volpin D, Bressan GM. Collagen VI deficiency induces early onset myopathy in the mouse: an animal model for Bethlem myopathy. Hum Mol Genet. (1998);7:2135–2140. doi: 10.1093/hmg/7.13.2135.
26. Takano H, Komuro I, Oka T, et al. The Rho family G proteins play a critical role in muscle differentiation. Mol Cell Biol. (1998);18:1580–1589. doi: 10.1128/MCB.18.3.1580.
27. Schwander M, Leu M, Stumm M, et al. Beta1 integrins regulate myoblast fusion and sarcomere assembly. Dev Cell. (2003);4:673–685. doi: 10.1016/S1534-5807(03)00118-7.
28. Andersen NB, Malmlöf K, Johansen PB, Andreassen TT, Ørtoft G, Oxlund H. The growth hormone secretagogue ipamorelin counteracts glucocorticoid-induced decrease in bone formation of adult rats. Growth Horm IGF Res. 2001;11(5):266-72.
29. Mericq V, Cassorla F, Salazar T, et al. Effects of eight months treatment with graded doses of a growth hormone (GH)-releasing peptide in GH-deficient children. J Clin Endocrinol Metab. 1998;83(7):2355-60.
30. Bellone J, Ghizzoni L, Aimaretti G, et al. Growth hormone-releasing effect of oral growth hormone-releasing peptide 6 (GHRP-6) administration in children with short stature. Eur J Endocrinol. 1995;133(4):425-9.
31. Ghigo E, Arvat E, Muccioli G, Camanni F. Growth hormone-releasing peptides. Eur J Endocrinol. 1997;136(5):445-60.
32. Mericq V, Cassorla F, Bowers CY, Avila A, Gonen B, Merriam GR. Changes in appetite and body weight in response to long-term oral administration of the ghrelin agonist GHRP-2 in growth hormone deficient children. J Pediatr Endocrinol Metab. 2003;16:981–985.
33. Pihoker C, Kearns GL, French D, Bowers CY. Pharmacokinetics and pharmacodynamics of growth hormone-releasing peptide-2: a phase I study in children. J Clin Endocrinol Metab. 1998;83(4):1168–1172.
34. Johansen PB, Nowak J, Skjaerbaek C, et al. Ipamorelin, a new growth-hormone-releasing peptide, induces longitudinal bone growth in rats. Growth Horm IGF Res. 1999;9(2):106-13.
35. Svensson J, Lall S, Dickson SL, et al. The GH secretagogues ipamorelin and GH-releasing peptide-6 increase bone mineral content in adult female rats. J Endocrinol. 2000;165(3):569-77.
36. Svensson, J., Lall, S., Dickson, S. L., Bengtsson, B. A., Rømer, J., Ahnfelt-Rønne, I., Ohlsson, C., & Jansson, J. O. (2001). Effects of growth hormone and its secretagogues on bone. Endocrine, 14(1), 63–66. https://doi.org/10.1385/ENDO:14:1:063.
37. Guo S, Gao Q, Jiao Q, Hao W, Gao X, Cao JM. Gastric mucosal damage in water immersion stress: mechanism and prevention with GHRP-6. World J Gastroenterol. 2012;18(24):3145–3155.
38. Tack J, Depoortere I, Bisschops R, et al. Influence of ghrelin on interdigestive gastrointestinal motility in humans. Gut. 2006;55(3):327-33.
39. Haruta I, Fuku Y, Kinoshita K, et al. One-year intranasal application of growth hormone releasing peptide-2 improves body weight and hypoglycemia in a severely emaciated anorexia nervosa patient. Journal of Cachexia, Sarcopenia and Muscle. 2015;6(3):237-241. doi:10.1002/jcsm.12028.
40. Beck DE, Sweeney WB, Mccarter MD. Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. Int J Colorectal Dis. 2014;29(12):1527-34.
41. Depoortere I, De Winter B, Thijs T, De Man J, Pelckmans P, Peeters T. Comparison of the gastroprokinetic effects of ghrelin, GHRP-6 and motilin in rats in vivo and in vitro. Eur J Pharmacol. 2005;515(1–3):160–168.
42. Kitazawa T, De Smet B, Verbeke K, Depoortere I, Peeters TL. Gastric motor effects of peptide and non-peptide ghrelin agonists in mice in vivo and in vitro. Gut. 2005;54(8):1078–1084.
43. Xu L, Depoortere I, Tomasetto C, et al. Evidence for the presence of motilin, ghrelin, and the motilin and ghrelin receptor in neurons of the myenteric plexus. Regul Pept. 2005;124(1–3):119–125.
44. Greenwood-Van Meerveld B, Tyler K, Mohammadi E, Pietra C. Efficacy of ipamorelin, a ghrelin mimetic, on gastric dysmotility in a rodent model of postoperative ileus. Journal of Experimental Pharmacology. 2012;4:149-155. doi:10.2147/JEP.S35396.
45. Qiu WC, Wang ZG, Wang WG, Yan J, Zheng Q. Gastric motor effects of ghrelin and growth hormone releasing peptide 6 in diabetic mice with gastroparesis. World J Gastroenterol. 2008;14(9):1419-24.
46. Venkova K, Mann W, Nelson R, Greenwood-Van Meerveld B. Efficacy of ipamorelin, a novel ghrelin mimetic, in a rodent model of postoperative ileus. J Pharmacol Exp Ther. 2009;329(3):1110–1116.
47. Fazio S. Sabatini D. Capaldo B. et al. A preliminary study of growth hormone in the treatment of dilated cardiomyopathy N. Engl. J. Med.  1996 334 809 814.
48. Broglio F. Guarracino F. Benso A. et al. Effects of acute hexarelin administration on cardiac performance in patients with coronary artery disease during by-pass surgery Eur. J. Pharmacol.  2002 448 193 200.
49. Bisi G, Podio V, Valetto MR, Broglio F, Bertuccio G, Del Rio G, Arvat E, Boghen MF, Deghengi R, Muccioli G, Ong H, Ghigo E 1999 Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH-releasing peptide, in humans. J Endocrinol Invest 22:266–272.
50. Bisi G, Podio V, Valetto MR, et al. Acute cardiovascular and hormonal effects of GH and hexarelin, a synthetic GH–releasing peptide, in humans. J Endocrinol Invest 1999 ; 224 : 266-72.
51. Valetto MR, Podio V, Broglio F et al. The acute administration of Hexarelin, a peptidyl GH secretagogues, has GH-independent, positive inotropic effect in humans. In : Hormones and the Heart, Naples, Italy 1998 ; abs. p. 54.
52. Ghigo E, Arvat E, Gianotti L et al. Growth hormone-releasing activity of Hexarelin, a new synthetic hexapeptide, after intravenous, subcutaneous, intranasal and oral administration in man. J Clin Endocrinol Metab 1994 ; 78 : 693-8.
53. Rahim A, O’Neill PA, Shalet SM. Growth hormone status -during long-term hexarelin therapy. J Clin Endocrinol Metab 1998 ; 83 : 1644-9.
54. Vasan RS, Sullivan LM, D’agostino RB, et al. Serum insulin-like growth factor I and risk for heart failure in elderly individuals without a previous myocardial infarction: the Framingham Heart Study. Ann Intern Med. 2003;139(8):642-8.
55. Locatelli V. Rossoni G. Schweiger F. et al. Growth hormone independent cardioprotective effects of hexarelin in the rat Endocrinology  1999 140 4024 4031.
56. Tivesten A. Bollano E. Caidahl K. et al. The growth hormone secretagogue hexarelin improves cardiac function in rats after experimental myocardial infarction Endocrinology  2000 141 60 66.
57. Xu X.B. Cao J.M. Pang J.J. et al. The positive inotropic and calcium-mobilizing effects of growth hormone-releasing peptides on rat heart Endocrinology  2003 144 5050 5057.
58. Titterington JS, Sukhanov S, Higashi Y, Vaughn C, Bowers C, Delafontaine P. Growth Hormone-Releasing Peptide-2 Suppresses Vascular Oxidative Stress in ApoE−/− Mice But Does Not Reduce Atherosclerosis. Endocrinology. 2009;150(12):5478-5487. doi:10.1210/en.2009-0283.
59. Iwase M. Kanazawa H. Kato Y. et al. Growth-hormone releasing peptide can improve left ventricular dysfunction and attenuate dilation in dilated cardiomyopathic hamsters Cardiovasc. Res.  2004 61 30 38.
60. Shen Y.T. Lynch J.J. Hargreaves R.J. Gould R.J. A growth hormone secretagogue prevents ischemic-induced mortality independently of the growth hormone pathway in dogs with chronic dilated cardiomyopathy J. Pharmacol. Exp. Ther. 2003 306 815 820.
61. Berlanga J, Cibrian D, Guevara L, et al. Growth-hormone-releasing peptide 6 (GHRP6) prevents oxidant cytotoxicity and reduces myocardial necrosis in a model of acute myocardial infarction. Clin Sci. 2007;112(4):241-50.
62. Catalina PF, Mallo F, Andrade MA, García-mayor RV, Diéguez C. Growth hormone (GH) response to GH-releasing peptide-6 in type 1 diabetic patients with exaggerated GH-releasing hormone-stimulated GH secretion. J Clin Endocrinol Metab. 1998;83(10):3663-7.
63. Villares R, Kakabadse D, Juarranz Y, Gomariz RP, Martínez-a C, Mellado M. Growth hormone prevents the development of autoimmune diabetes. Proc Natl Acad Sci USA. 2013;110(48):E4619-27.
64. Adeghate E, Ponery AS. Mechanism of ipamorelin-evoked insulin release from the pancreas of normal and diabetic rats. Neuro Endocrinol Lett. 2004;25(6):403-6.
65. Granado M, García-cáceres C, Tuda M, Frago LM, Chowen JA, Argente J. Insulin and growth hormone-releasing peptide-6 (GHRP-6) have differential beneficial effects on cell turnover in the pituitary, hypothalamus and cerebellum of streptozotocin (STZ)-induced diabetic rats. Mol Cell Endocrinol. 2011;337(1-2):101-13.
66. Johansen PB, Segev Y, Landau D, Phillip M, Flyvbjerg A. Growth hormone (GH) hypersecretion and GH receptor resistance in streptozotocin diabetic mice in response to a GH secretagogue. Exp Diabesity Res. 2003;4(2):73-81.
67. Bailey CJ, Wilkes LC, Flatt PR, Conlon JM, Buchanan KD. Effects of growth hormone-releasing hormone on the secretion of islet hormones and on glucose homeostasis in lean and genetically obese-diabetic (ob/ob) mice and normal rats. J Endocrinol (1989) 123(1):19–24.10.1677/joe.0.1230019.
68. Ludwig B, Ziegler CG, Schally AV, Richter C, Steffen A, Jabs N, et al. Agonist of growth hormone-releasing hormone as a potential effector for survival and proliferation of pancreatic islets. Proc Natl Acad Sci U S A (2010) 107(28):12623–8.10.1073/pnas.1005098107.
69. Ludwig B, Rotem A, Schmid J, Weir GC, Colton CK, Brendel MD, et al. Improvement of islet function in a bioartificial pancreas by enhanced oxygen supply and growth hormone releasing hormone agonist. Proc Natl Acad Sci U S A (2012) 109(13):5022–7.10.1073/pnas.1201868109.
70. Zhang X, Cui T, He J, Wang H, Cai R, Popovics P, et al. Beneficial effects of growth hormone-releasing hormone agonists on rat INS-1 cells and on streptozotocin-induced NOD/SCID mice. Proc Natl Acad Sci U S A (2015) 112(44):13651–6.10.1073/pnas.1518540112.
71. Schubert U, Schmid J, Lehmann S, Zhang XY, Morawietz H, Block NL, et al. Transplantation of pancreatic islets to adrenal gland is promoted by agonists of growth-hormone-releasing hormone. Proc Natl Acad Sci U S A (2013) 110(6):2288–93.10.1073/pnas.1221505110.
72. Schmid J, Ludwig B, Schally AV, Steffen A, Ziegler CG, Block NL, et al. Modulation of pancreatic islets-stress axis by hypothalamic releasing hormones and 11beta-hydroxysteroid dehydrogenase. Proc Natl Acad Sci U S A (2011) 108(33):13722–7.10.1073/pnas.1110965108.
73. Perboni S, Bowers C, Kojima S, Asakawa A, Inui A. Growth hormone releasing peptide 2 reverses anorexia associated with chemotherapy with 5-fluoruracil in colon cancer cell-bearing mice. World J Gastroenterol. 2008;14(41):6303–6305.
74. Abbassi V, Bellanti    Humoral a cell-mediated   immunity in growth hormone-deficient  children: effect of therapy with human growth hormone. Pediat Res 1985; 19: 299-301.
75. Rapaport R, Oleske J, Aldich H, Salomon S, Delfaus C, Denny T. Suppression of immune function in   growth   hormone-deficient   children   during   treatment   with   human   growth hormone. J Pediatr 1986; 109; 434-439.
76. Granado M, Priego T, Martin AI, Villanua MA, Lopez-Calderon A. Anti-inflammatory effect of the ghrelin agonist growth hormone-releasing peptide-2 (GHRP-2) in arthritic rats. Am J Physiol Endocrinol Metab. 2005;288(3):E486-E492.
77. Cao Y, Tang J, Yang T, et al. Cardioprotective effect of ghrelin in cardiopulmonary bypass involves a reduction in inflammatory response. PLoS One. 2013;8(1):e55021.
78. García Del Barco D, Montero E, Coro-Antich RM, et al. Coadministration of epidermal growth factor and growth hormone releasing peptide-6 improves clinical recovery in experimental autoimmune encephalitis. Restor Neurol Neurosci. 2011;29(4):243–252.
79. García Del Barco D, Perez-Saad H, Rodriguez V, et al. Therapeutic effect of the combined use of growth hormone releasing peptide-6 and epidermal growth factor in an axonopathy model. Neurotox Res. 2011;19(1):195–209.
80. Garcia Del Barco-Herrera D, Martinez NS, Coro-Antich RM, et al. Epidermal growth factor and growth hormone-releasing peptide-6: combined therapeutic approach in experimental stroke. Restor Neurol Neurosci. 2013;31(2):213–223.
81. Subiros N, Perez-Saad HM, Berlanga JA, et al. Assessment of dose-effect and therapeutic time window in preclinical studies of rhEGF and GHRP-6 coadministration for stroke therapy. Neurol Res. 2015;38(3):187–195.
82. Martínez R, Hernández L, Gil L, et al. Growth hormone releasing peptide-6 enhanced antibody titers against subunit antigens in mice (BALB/c), tilapia (Oreochromis niloticus) and African catfish (Clarias gariepinus). Vaccine. 2017;35(42):5722-5728.
83. Corpas E, Harman SM, Blackman MR. Human growth hormone and human aging. Endocrin Rev. 1993;14:20–39.
84. Sonntag WE, Meites J. Decline in GH secretion in aging animals and man. In: Everett AV, Walton JR, editors. Regulation of neuroendocrine aging. Karger; Basel: 1988. pp. 111–124.
85. Uberti ECD, Ambrosio MR, Cella SG, Margutti AR, Trasforini G, Rigamonti AE, Petrone E, Muller EE. Defective hypothalamic growth hormone (GH)-releasing hormone activity may contribute to declining GH secretion with age in man. J Clin Endocinol Metab. 1997;82:2885–2888.
86. Russell-Aulet M, Jaffe CA, Demott-Friberg R, Barkan AL. In vivo semiquantification of hypothalamic growth hormone-releasing hormone (GHRH) output in humans: Evidence for relative GHRH deficiency in aging. J Clin Endocinol Metab. 1999;84:3490–3497.
87. Gala RR. Prolactin and growth hormone in the regulation of the immune system. Proc Soc Exp Biol Med. 1991;198(1):513-27.
88. Gelato MC. Growth hormone-insulinlike growth factor I and immune function. Trends Endocrinol Metab. 1993;4(3):106-10.
89. Available at https://clinicaltrials.gov/ct2/show/NCT00663611.
90. Takagi K, Suzuki F, Barrow RE, Wolf SE, Kobayashi M, Herndon DN. Growth hormone improves immune function and survival in burned mice infected with herpes simplex virus type 1. J Surg Res. 1997;69(1):166-70.
91. Gelato MC. Aging and immune function: a possible role for growth hormone. Horm Res. 1996;45(1-2):46-9.
92. Rapaport R, Oleske J, Ahdieh H, Solomon S, Delfaus C, Denny T. Suppression of immune function in growth hormone-deficient children during treatment with human growth hormone. J Pediatr. 1986;109(3):434-9.
93. Meazza C, Pagani S, Travaglino P, Bozzola M. Effect of growth hormone (GH) on the immune system. Pediatr Endocrinol Rev. 2004;1 Suppl 3:490-5.
94. Manfredi R, Tumietto F, Azzaroli L, Zucchini A, Chiodo F, Manfredi G. Growth hormone (GH) and the immune system: impaired phagocytic function in children with idiopathic GH deficiency is corrected by treatment with biosynthetic GH. J Pediatr Endocrinol. 1994;7(3):245-51.
95. Tesselaar K, Miedema F. Growth hormone resurrects adult human thymus during HIV-1 infection. J Clin Invest. 2008;118(3):844-7.
96. Meazza C, Pagani S, Travaglino P, Bozzola M. Effect of growth hormone (GH) on the immune system. Pediatr Endocrinol Rev. 2004;1 Suppl 3:490-5.
97. Meazza C, Pagani S, Travaglino P, Bozzola M. Effect of growth hormone (GH) on the immune system. Pediatr Endocrinol Rev. 2004;1 Suppl 3:490-5.
98. Saxena GB, Saxena RK, Adler WH. Regulation of natural killer activity in vivo. III. Effect of   hypophysectomy   and   growth   hormone  treatment  on   the   natural   killer   activity   of   the mouse spleen cell population. Int Arch Allergy Appl Immunol 1982; 67: 169-174.
99. Kiess W, Malozowski S, Gelato M,   Butenandt  O, Doerr H, Crisp B, Eisl   E,   Maluish   A, Belohradsky      Lymphocyte   subset   distribution   and  natural   killer   activity  in   growth hormone deficiency before and during short-term treatment with growth hormone releasing hormone. Clin Immunol Immunopathol 1988; 48: 85-94.
100. Bozzola M,   De   Amici   M,   Zecca   M,   Schimpff     Rapaport   M.   Modulating   effect   of growth hormone on tumor necrosis factor-α and interleukin-1β. Eur J Endocrinol 1998; 139: 640-643.
101. Bozzola M, De Benedetti F, De Amici M, Jouret B,  Travaglino   P,   Pagani  S, Conte F & Tauber    Stimulating   effect  of  growth   hormone on   cytokine  release in   children.  Eur  J Endocrinol 2003; 149: 1-5.
102. Serri O, St-Jacques P, Sartippour M, Renier G. Alterations of monocyte function in patients with growth hormone deficiency: effect of substitutive GH therapy. J Clin Endocrinol Metab 1999; 84: 58-63.
103. Kelley, K. W.. 1991. Growth hormone in immunobiology. R. Ader, and D. L. Felton, and N. Cohen, eds. Psychoneuroimmunology 2nd Ed.377 Academic Press, New York.
104. Murphy, W. J., R. Hallgeir, D. L. Longo. 1995. Effects of growth hormone and prolactin in immune development and function. Life Sci. 57: 1.
105. Clark, R.. 1997. The somatogenic hormones and insulin-like growth factor-1: stimulators of lymphopoiesis and immune function. Endocr. Rev. 18: 157.
106. Smith, P. E.. 1930. Effect of hypophysectomy upon the involution of the thymus in the rat. Anat. Rec. 47: 119.
107. Duquesnoy, R. J., G. M. Pederson. 1981. Immunology and hematologic deficiencies of the hipopituitary dwarf mouse. M. E. Gershwin, and B. Merchant, eds. In Immunology Defects in Laboratory Animals Vol. 1: 309 Plenum, New York.
108. Gala, R. R., E. M. Shevach. 1993. Influence of prolactin and growth hormone on the activation of dwarf mouse lymphocytes in vivo. Proc. Soc. Exp. Biol. Med. 204: 224.
109. Murphy, W. J., S. K. Durum, D. L Longo. 1992. Human growth hormone promotes engraftment of murine or human T cells in severe combined immunodeficient mice. Proc. Natl. Acad. Sci. USA 89: 4481.
110. Taub, D. D., G. Tsarfaty, A. R. Lloyd, S. K. Durum, D. L. Longo, W. J. Murphy. 1994. Growth hormone promotes human T cells adhesion and migration to both human and murine matrix proteins in vitro and directly promotes xenogeneic engraftment. J. Clin. Inv. 94: 293.
111. Koo GC, Huang C, Camacho R, et al. Immune enhancing effect of a growth hormone secretagogue. J Immunol. 2001;166(6):4195-201.
112. Hersch EC, Merriam GR. Growth hormone (GH)–releasing hormone and GH secretagogues in normal aging: Fountain of Youth or Pool of Tantalus? Clinical Interventions in Aging. 2008;3(1):121-129.
113. Aleman A, Verhaar HJ, De haan EH, et al. Insulin-like growth factor-I and cognitive function in healthy older men. J Clin Endocrinol Metab. 1999;84(2):471-5.
114. Vitiello MV, Schwartz RS, Buchner KE, et al. Treating age-related changes in somatotrophic hormones, sleep, and cognition. Dialogs in Clinical Neuroscience. 2001;3:229–36.
115. Vitiello MV, Moe KE, Merriam GR, Mazzoni G, Buchner DH, Schwartz RS. Growth hormone releasing hormone improves the cognition of healthy older adults. Neurobiol Aging. 2006;27(2):318-23.
116. Friedman SD, Baker LD, Borson S, et al. Growth hormone-releasing hormone effects on brain γ-aminobutyric acid levels in mild cognitive impairment and healthy aging. JAMA Neurol. 2013;70(7):883-90.
117. Kim SW, Her SJ, Park SJ, et al. Ghrelin stimulates proliferation and differentiation and inhibits apoptosis in osteoblastic MC3T3-E1 cells. Bone. 2005;37(3):359-69.
118. Kim YS, Choi DH, Block ML, et al. A pivotal role of matrix metalloproteinase-3 activity in dopaminergic neuronal degeneration via microglial activation. FASEB J. 2007;21(1):179-87.
119. Banks WA, Tschöp M, Robinson SM, Heiman ML. Extent and direction of ghrelin transport across the blood-brain barrier is determined by its unique primary structure. J Pharmacol Exp Ther. 2002;302(2):822-7.
120. Chung H, Seo S, Moon M, Park S. Phosphatidylinositol-3-kinase/Akt/glycogen synthase kinase-3 beta and ERK1/2 pathways mediate protective effects of acylated and unacylated ghrelin against oxygen-glucose deprivation-induced apoptosis in primary rat cortical neuronal cells. J Endocrinol. 2008;198(3):511-21.
121. García-cáceres C, Lechuga-sancho A, Argente J, Frago LM, Chowen JA. Death of hypothalamic astrocytes in poorly controlled diabetic rats is associated with nuclear translocation of apoptosis inducing factor. J Neuroendocrinol. 2008;20(12):1348-60.
122. Frago LM, Pañeda C, Dickson SL, Hewson AK, Argente J, Chowen JA. Growth hormone (GH) and GH-releasing peptide-6 increase brain insulin-like growth factor-I expression and activate intracellular signaling pathways involved in neuroprotection. Endocrinology. 2002;143(10):4113-22.
123. Zhang Y, Bhavnani BR. Glutamate-induced apoptosis in neuronal cells is mediated via caspase-dependent and independent mechanisms involving calpain and caspase-3 proteases as well as apoptosis inducing factor (AIF) and this process is inhibited by equine estrogens. BMC Neurosci. 2006;7:49.
124. Halem HA, Taylor JE, Dong JZ, et al. A novel growth hormone secretagogue-1a receptor antagonist that blocks ghrelin-induced growth hormone secretion but induces increased body weight gain. Neuroendocrinology. 2005;81(5):339-49.
125. Zigman JM, Nakano Y, Coppari R, et al. Mice lacking ghrelin receptors resist the development of diet-induced obesity. J Clin Invest. 2005;115(12):3564-72.
126. Arnoult D, Karbowski M, Youle RJ. Caspase inhibition prevents the mitochondrial release of apoptosis-inducing factor. Cell Death Differ. 2003;10(7):845-9.
127. Rungger-brändle E, Dosso AA, Leuenberger PM. Glial reactivity, an early feature of diabetic retinopathy. Invest Ophthalmol Vis Sci. 2000;41(7):1971-80.
128. Arnoult D, Karbowski M, Youle RJ. Caspase inhibition prevents the mitochondrial release of apoptosis-inducing factor. Cell Death Differ. 2003;10(7):845-9.
129. Jiang Z, Zhang Y, Chen X, et al. Activation of Erk1/2 and Akt in astrocytes under ischemia. Biochem Biophys Res Commun. 2002;294(3):726-33.
130. Jiang H, Betancourt L, Smith RG. Ghrelin amplifies dopamine signaling by cross talk involving formation of growth hormone secretagogue receptor/dopamine receptor subtype 1 heterodimers. Mol Endocrinol. 2006;20(8):1772-85.
131. Frago LM, Pañeda C, Dickson SL, Hewson AK, Argente J, Chowen JA. Growth hormone (GH) and GH-releasing peptide-6 increase brain insulin-like growth factor-I expression and activate intracellular signaling pathways involved in neuroprotection. Endocrinology. 2002;143(10):4113-22.
132. Baserga R, Hongo A, Rubini M, Prisco M, Valentini SB 1997 The IGF-I receptor in cell growth, transformation and apoptosis. Biochim Biophys Acta 1332:F105–F126.
133. Kulik G, Klippel A, Weber MJ 1997 Antiapoptotic signalling by the insulin-like growth factor I receptor, phosphatidylinositol 3-kinase and Akt. Mol Cell Biol 17:1595–1606.
134. Chrysis D, Calikoglu AS, Ye P, D’Ercole AJ 2001 Insulin-like growth factor-I overexpression attenuates cerebellar apoptosis by altering the expression of Bcl family proteins in a developmentally specific manner. J Neurosci 21:1481–1489.
135. Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA 1996 Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15:6541–6551.
136. Dudek H, Datta SR, Franke TF, Birnbaum MJ, Yao R, Cooper GM, Segal RA, Kaplan DR, Greenberg ME 1997 Regulation of neural survival by the serine-threonine protein kinase Akt. Science 275:661–668.
137. Mehrhof FB, Muller FU, Bergmann MW, Li P, Wang Y, Schmitz W, Dietz R, von Harsdorf R 2001 In cardiomyocyte hypoxia, insulin-like growth factor-I-induced antiapoptotic signaling requires phosphatidylinositol-3-OH-kinase-dependent and mitogen-activated protein kinase-dependent activation of the transcription factor cAMP response element-binding protein. Circulation 104:2088–2094.
138. Gleichmann M, Weller M, Schuyltz JB 2000 Insulin-like growth factor-1-mediated protection from neuronal apoptosis is linked to phosphorylation of the pro-apoptotic protein BAD but not to inhibition of cytochrome c translocation in rat cerebellar neurons. Neurosci Lett 282:69–72.
139. Peruzzi F, Prisco M, Dews M, Salomoni P, Grassilli E, Romano G, Calabretta B, Baserga R 1999 Multiple signaling pathways of the insulin-like growth factor 1 receptor in protection from apoptosis. Mol Cell Biol 19:7203–7215.
140. Kulik G, Weber MJ 1998 Akt-dependent and -independent survival signaling pathways utilized by insulin-like growth factor I. Mol Cell Biol 18:6711–6718.
141. Harada H, Andersen JS, Mann M, Terada N, Korsmeyer SJ 2001 p70S6 kinase signals cell survival as well as growth, inactivating the pro-apoptotic molecule BAD. Proc Natl Acad Sci USA 98:9666–9670.
142. Desbois-Moutho C, Cadoret A, Blivet-Van Eggelpoel MJ, Bertrand F, Cherqui G, Perret C, Capeau J 2001 Insulin and IGF-1 stimulate the β-catenin pathway through two signalling cascades involving GSK-3β inhibition and Ras activation. Oncogene 20:252–259.
143. Park BC, Kido Y, Accili D 1999 Differential signaling of insulin and IGF-1 receptors to glycogen synthesis in murine hepatocytes. Biochemistry 38:7517–7523.
144. Cui H, Meng Y, Bulleit RF 1998 Inhibition of glycogen synthase kinase 3β activity regulates proliferation of cultured cerebellar granule cells. Brain Res Dev Brain Res 111:177–188.
145. Tamatani M, Ogawa S, Nuñez G, Tokyama M 1998 Growth factors prevent changes in Bcl-2 and Bax expression and neuronal apoptosis induced by nitric oxide. Cell Death Differ 5:911–919.
146. Baker NlL, Carlo Russo V, Bernard O, D’Ercole AJ, Werther GA 1999 Interactions between bcl-2 and the IGF-I system control apoptosis in the developing mouse brain. Brain Res Dev Brain Res 118:109–118.
147. Du K, Montminy M 1998 CREB is a regulatory target for the protein kinase Akt/PKB. J Biol Chem 273:32377.
148. Pugazhenthi S, Nesterova A, Sable C, Heidenreich KA, Boxer LM, Heasly LE, Reusch JE 2000 Akt/protein kinase B upregulates Bcl-2 expression through cAMP-response element-binding protein. J Biol Chem 275:10761–10766.
149. Brod M, Pohlman B, Højbjerre L, Adalsteinsson JE, Rasmussen MH. Impact of adult growth hormone deficiency on daily functioning and well-being. BMC Research Notes. 2014;7:813. doi:10.1186/1756-0500-7-813.
150. Maggi M, Buvat J, Corona G, Guay A, Torres LO. Hormonal causes of male sexual dysfunctions and their management (hyperprolactinemia, thyroid disorders, GH disorders, and DHEA). J Sex Med. 2013;10(3):661-77.
151. Ginzburg E, Lin A, Sigler M, Olsen D, Klimas N, Mintz A. Testosterone and growth hormone normalization: a retrospective study of health outcomes. Journal of multidisciplinary healthcare. 2008;1:79-86.
152. Brod M, Højbjerre L, Adalsteinsson JE, Rasmussen MH. Assessing the impact of growth hormone deficiency and treatment in adults: development of a new disease-specific measure. J Clin Endocrinol Metab. 2014;99(4):1204-12.
153. Available at https://www.researchgate.net/publication/12600670_Effects_of_growth_hormone_on_male_reproductive_functions.
154. Galdiero M, Pivonello R, Grasso LF, Cozzolino A, Colao A. Growth hormone, prolactin, and sexuality. J Endocrinol Invest. 2012;35(8):782-94.
155. Becker AJ, Uckert S, Stief CG, et al. Possible role of human growth hormone in penile erection. J Urol. 2000;164(6):2138-42.
156. Becker AJ, Uckert S, Stief CG, et al. Serum levels of human growth hormone during different penile conditions in the cavernous and systemic blood of healthy men and patients with erectile dysfunction. Urology. 2002;59(4):609-14.
157. Otunctemur A, Ozbek E, Sahin S, et al. Low serum insulin-like growth factor-1 in patients with erectile dysfunction. Basic and Clinical Andrology. 2016;26:1. doi:10.1186/s12610-015-0028-x.
158. Rajfer J. Growth Factors and Gene Therapy for Erectile Dysfunction. Reviews in Urology. 2000;2(1):34.
159. Pastuszak AW, Liu JS, Vij A. IGF-1 levels are significantly correlated with patient-reported measures of sexual function. International journal of impotence research. 2011; 23(5):220-6.
160. Pastuszak AW, Liu JS, Vij A, et al. IGF-1 levels are significantly correlated with patient-reported measures of sexual function. Int J Impot Res. 2011;23(5):220-6.
161. El-Sakka AI, Lin CS, Chui RM, Dahiya R, Lue TF. Effects of diabetes on nitric oxide synthase and growth factor genes and protein expression in an animal model. Int J Impot Res. 1999;11:123–32. doi: 10.1038/sj.ijir.3900392.
162. Soh J, Katsuyama M, Ushijima S, Mizutani Y, Kawauchi A, Yabe-Nishimura C, et al. Localization of increased insulin-like growth factor binding protein-3 in diabetic rat penis: Implications for erectile dysfunction. Urology. 2007;70:1019–23. doi: 10.1016/j.urology.2007.07.057.
163. Pu XY, Zheng XG, Zhang Y, Xiao HJ, Xu ZP, Liu JM, et al. Higher expression of mRNA and protein of insulin-like growth factor binding protein-3 in old rat penile tissues: implications for erectile dysfunction. J Sex Med. 2011;8:2181–90. doi: 10.1111/j.1743-6109.2011.02318.x.
164. Khorram O, Laughlin GA, Yen SS. Endocrine and metabolic effects of long-term administration of [Nle27]growth hormone-releasing hormone-(1-29)-NH2 in age-advanced men and women. J Clin Endocrinol Metab. 1997;82(5):1472-9.
165. Rubinek T, Rubinfeld H, Hadani M, Barkai G, Shimon I. Nitric oxide stimulates growth hormone secretion from human fetal pituitaries and cultured pituitary adenomas. Endocrine. 2005;28(2):209-16.
166. Valverde I, Peñalva A, Ghigo E, Casanueva FF, Dieguez C. Involvement of nitric oxide in the regulation of growth hormone secretion in dogs. Neuroendocrinology. 2001;74(4):213-9.
167. Rigamonti AE, Cella SG, Marazzi N, Müller EE. Nitric oxide modulation of the growth hormone-releasing activity of Hexarelin in young and old dogs. Metab Clin Exp. 1999;48(2):176-82.
168. Doi SQ, Jacot TA, Sellitti DF, et al. Growth hormone increases inducible nitric oxide synthase expression in mesangial cells. J Am Soc Nephrol. 2000;11(8):1419-25.
169. Available at http://erj.ersjournals.com/content/31/4/815.
170. Deniz Tuncel, Fatma Inanc Tolun, and Ismail Toru, “Serum Insulin-Like Growth Factor-1 and Nitric Oxide Levels in Parkinson’s Disease,” Mediators of Inflammation, vol. 2009, Article ID 132464, 4 pages, 2009.
171. Available at https://clinicaltrials.gov/ct2/show/NCT00470002.
172. Böger RH , Skamira C , Bode-Böger SM , Brabant G , von zur Muhlen A , Frolich JC. 1996. Nitric oxide may mediate the hemodynamic effects of recombinant growth hormone in patients with acquired growth hormone deficiency. A double-blind, placebo-controlled study. J Clin Invest 98:2706–2713.
173. Thum T , Fleissner F , Klink I , Tsikas D , Jakob M , Bauersachs J , Stichtenoth DO. 2007. Growth hormone treatment improves markers of systemic nitric oxide bioavailability via insulin-like growth factor-I. J Clin Endocrinol Metab 92:4172–4179.
174. Mani maran RR, Sivakumar R, Ravisankar B, et al. Growth hormone directly stimulates testosterone and oestradiol secretion by rat Leydig cells in vitro and modulates the effects of LH and T3. Endocr J. 2000;47(2):111-8.
175. Ho KY, Evans WS, Blizzard RM, et al. Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations. J Clin Endocrinol Metab. 1987;64(1):51-8.
176. Argiolas A, Melis MR. Central control of penile erection: role of the paraventricular nucleus of the hypothalamus. Prog Neurobiol. 2005;76(1):1-21.
177. Kim KS, Bae WJ, Kim SJ, et al. Improvement of erectile dysfunction by the active pepide from Urechis unicinctus by high temperature/pressure and ultra – wave assisted lysis in Streptozotocin Induced Diabetic Rats. International Brazilian Journal of Urology: official journal of the Brazilian Society of Urology. 2016;42(4):825-837. doi:10.1590/S1677-5538.IBJU.2015.0606.
178. Wessells H, Blevins JE, Vanderah TW. Melanocortinergic control of penile erection. Peptides. 2005;26(10):1972-1977. doi:10.1016/j.peptides.2004.11.035.
179. Melis MR, Argiolas A. Central oxytocinergic neurotransmission: a drug target for the therapy of psychogenic erectile dysfunction. Curr Drug Targets. 2003;4(1):55-66.
180. Andersson KE. Mechanisms of penile erection and basis for pharmacological treatment of erectile dysfunction. Pharmacol Rev. 2011;63(4):811-59.
181. Andersson KE. Pharmacology of penile erection. Pharmacol Rev. 2001;53(3):417-50.
182. Decaluwé K, Pauwels B, Verpoest S, Van de voorde J. New therapeutic targets for the treatment of erectile dysfunction. J Sex Med. 2011;8(12):3271-90.
183. Ryu B, Kim M, Himaya SWA, Kang KH, Kim SK. Statistical optimization of high temperature/pressure and ultra-wave assisted lysis of Urechis unicinctus for the isolation of active peptide which enhance the erectile function in vitro. Process Biochemistry. 2014;49:148–153.
184. Liu Q, Jia Z, Duan L, Xiong J, Wang D, Ding Y. Functional peptides for cartilage repair and regeneration. American Journal of Translational Research. 2018;10(2):501-510.
185. Hastar N, Arslan E, Guler MO, Tekinay AB. Peptide-Based Materials for Cartilage Tissue Regeneration. Adv Exp Med Biol. 2017;1030:155-166.
186. Wang W, Rigueur D, Lyons KM. TGFbeta signaling in cartilage development and maintenance. Birth Defects Res C Embryo Today. 2014;102:37–51.
187. Lam HJ, Li S, Lou N, Chu J, Bhatnagar RS. Synthetic peptides cytomodulin-1 (CM-1) and cytomodulin-2 (CM-2) promote collagen synthesis and wound healing in vitro. Conf Proc IEEE Eng Med Biol Soc. 2004;7:5028–5030.
188. Basu S, Kumar M, Chansuria JP, Singh TB, Bhatnagar R, Shukla VK. Effect of Cytomodulin-10 (TGF-beta1 analogue) on wound healing by primary intention in a murine model. Int J Surg. 2009;7:460–465.
189. Mittal A, Kumar R, Parsad D, Kumar N. Cytomodulin-functionalized porous PLGA particulate scaffolds respond better to cell migration, actin production and wound healing in rodent model. J Tissue Eng Regen Med. 2014;8:351–36.
190. Shao Z, Zhang X, Pi Y, Wang X, Jia Z, Zhu J, Dai L, Chen W, Yin L, Chen H, Zhou C, Ao Y. Polycaprolactone electrospun mesh conjugated with an MSC affinity peptide for MSC homing in vivo. Biomaterials. 2012;33:3375–3387.
191. Huang H, Zhang X, Hu X, Shao Z, Zhu J, Dai L, Man Z, Yuan L, Chen H, Zhou C, Ao Y. A functional biphasic biomaterial homing mesenchymal stem cells for in vivo cartilage regeneration. Biomaterials. 2014;35:9608–9619.
192. Meng Q, Man Z, Dai L, Huang H, Zhang X, Hu X, Shao Z, Zhu J, Zhang J, Fu X, Duan X, Ao Y. A composite scaffold of MSC affinity peptide-modified demineralized bone matrix particles and chitosan hydrogel for cartilage regeneration. Sci Rep. 2015;5:17802.
193. Shao Z, Zhang X, Pi Y, Yin L, Li L, Chen H, Zhou C, Ao Y. Surface modification on polycaprolactone electrospun mesh and human decalcified bone scaffold with synovium-derived mesenchymal stem cells-affinity peptide for tissue engineering. J Biomed Mater Res A. 2015;103:318–329.
194. Webb DJ, Roadcap DW, Dhakephalkar A, Gonias SL. A 16-amino acid peptide from human alpha2-macroglobulin binds transforming growth factor-beta and platelet-derived growth factor-BB. Protein Sci. 2000;9:1986–1992.
195. Shah RN, Shah NA, Del Rosario Lim MM, Hsieh C, Nuber G, Stupp SI. Supramolecular design of self-assembling nanofibers for cartilage regeneration. Proc Natl Acad Sci U S A. 2010;107:3293–3298.
196. Chow LW, Armgarth A, St-Pierre JP, Bertazzo S, Gentilini C, Aurisicchio C, McCullen SD, Steele JA, Stevens MM. Peptide-directed spatial organization of biomolecules in dynamic gradient scaffolds. Adv Healthc Mater. 2014;3:1381–1386.
197. Parmar PA, Chow LW, St-Pierre JP, Horejs CM, Peng YY, Werkmeister JA, Ramshaw JA, Stevens MM. Collagen-mimetic peptide-modifiable hydrogels for articular cartilage regeneration. Biomaterials. 2015;54:213–225.
198. Recha-Sancho L, Semino CE. Heparin-based self-assembling peptide scaffold reestablish chondrogenic phenotype of expanded de-differentiated human chondrocytes. J Biomed Mater Res A. 2016;104:1694–1706.
199. Yamaoka H, Asato H, Ogasawara T, Nishizawa S, Takahashi T, Nakatsuka T, Koshima I, Nakamura K, Kawaguchi H, Chung UI, Takato T, Hoshi K. Cartilage tissue engineering using human auricular chondrocytes embedded in different hydrogel materials. J Biomed Mater Res A. 2006;78:1–11.
200. Kisiday J, Jin M, Kurz B, Hung H, Semino C, Zhang S, Grodzinsky AJ. Self-assembling peptide hydrogel fosters chondrocyte extracellular matrix production and cell division: implications for cartilage tissue repair. Proc Natl Acad Sci U S A. 2002;99:9996–10001.
201. Ruoslahti E, Pierschbacher MD. Arg-Gly-Asp: a versatile cell recognition signal. Cell. 1986;44:517–518.
202. Jeschke B, Meyer J, Jonczyk A, Kessler H, Adamietz P, Meenen NM, Kantlehner M, Goepfert C, Nies B. RGD-peptides for tissue engineering of articular cartilage. Biomaterials. 2002;23:3455–3463.
203. Kim HD, Heo J, Hwang Y, Kwak SY, Park OK, Kim H, Varghese S, Hwang NS. Extracellular-matrix-based and Arg-Gly-Asp-modified photopolymerizing hydrogels for cartilage tissue engineering. Tissue Eng Part A. 2015;21:757–766.
204. Frieboes RM, Murck H, Maier P, Schier T, Holsboer F, Steiger A. Growth hormone-releasing peptide-6 stimulates sleep, growth hormone, ACTH and cortisol release in normal man. Neuroendocrinology. 1995;61(5):584-9.
205. Moreno-reyes R, Kerkhofs M, L’hermite-balériaux M, Thorner MO, Van cauter E, Copinschi G. Evidence against a role for the growth hormone-releasing peptide axis in human slow-wave sleep regulation. Am J Physiol. 1998;274(5 Pt 1):E779-84.
206. Frieboes RM, Murck H, Antonijevic IA, Steiger A. Effects of growth hormone-releasing peptide-6 on the nocturnal secretion of GH, ACTH and cortisol and on the sleep EEG in man: role of routes of administration. J Neuroendocrinol. 1999;11(6):473-8.
207. Morselli LL, Nedeltcheva A, Leproult R, et al. Impact of growth hormone replacement therapy on sleep in adult patients with growth hormone deficiency of pituitary origin. European journal of endocrinology/European Federation of Endocrine Societies. 2013;168(5):10.1530/EJE-12-1037. doi:10.1530/EJE-12-1037.
208. Haqq AM, Stadler DD, Jackson RH, Rosenfeld RG, Purnell JQ, Lafranchi SH. Effects of growth hormone on pulmonary function, sleep quality, behavior, cognition, growth velocity, body composition, and resting energy expenditure in Prader-Willi syndrome. J Clin Endocrinol Metab. 2003;88(5):2206-12.
209. Van cauter E, Copinschi G. Interrelationships between growth hormone and sleep. Growth Horm IGF Res. 2000;10 Suppl B:S57-62.
210. Copinschi G, Nedeltcheva A, Leproult R, et al. Sleep disturbances, daytime sleepiness, and quality of life in adults with growth hormone deficiency. J Clin Endocrinol Metab. 2010;95(5):2195-202.
211. Davidson JR, Moldofsky H, Lue FA. Growth hormone and cortisol secretion in relation to sleep and wakefulness. Journal of Psychiatry and Neuroscience. 1991;16(2):96-102.
212. Moreno-reyes R, Kerkhofs M, L’hermite-balériaux M, Thorner MO, Van cauter E, Copinschi G. Evidence against a role for the growth hormone-releasing peptide axis in human slow-wave sleep regulation. Am J Physiol. 1998;274(5 Pt 1):E779-84.
213. Shah N, Rice T, Tracy D, et al. Sleep and Insulin-Like Growth Factors in the Cardiovascular Health Study. Journal of Clinical Sleep Medicine : JCSM : Official Publication of the American Academy of Sleep Medicine. 2013;9(12):1245-1251. doi:10.5664/jcsm.3260.
214. Mysliwiec V, Gill J, Matsangas P, Baxter T, Barr T, Roth BJ. IGF-1: a potential biomarker for efficacy of sleep improvement with automatic airway pressure therapy for obstructive sleep apnea?. Sleep Breath. 2015;19(4):1221-8.
215. Izumi S, Ribeiro-filho FF, Carneiro G, Togeiro SM, Tufik S, Zanella MT. IGF-1 Levels are Inversely Associated With Metabolic Syndrome in Obstructive Sleep Apnea. J Clin Sleep Med. 2016;12(4):487-93.
216. Izumi S, Ribeiro-Filho FF, Carneiro G, Togeiro SM, Tufik S, Zanella MT. IGF-1 Levels are Inversely Associated With Metabolic Syndrome in Obstructive Sleep Apnea. Journal of Clinical Sleep Medicine: JCSM: Official Publication of the American Academy of Sleep Medicine. 2016;12(4):487-493. doi:10.5664/jcsm.5672.
217. Rusch HL, Gill JM. Effect of Acute Sleep Disturbance and Recovery on Insulin-Like Growth Factor-1 (IGF-1): Possible Connections and Clinical Implications. Journal of Clinical Sleep Medicine: JCSM: Official Publication of the American Academy of Sleep Medicine. 2015;11(10):1245-1246. doi:10.5664/jcsm.5108.
218. Prinz PN, Moe KE, Dulberg EM, et al. Higher plasma IGF-1 levels are associated with increased delta sleep in healthy older men. J Gerontol A Biol Sci Med Sci. 1995;50(4):M222-6.
219. Damanti S, Bourron O, Doulazmi M, et al. Relationship between sleep parameters, insulin resistance and age-adjusted insulin like growth factor-1 score in non diabetic older patients. Blondeau B, ed. PLoS ONE. 2017;12(4):e0174876. doi:10.1371/journal.pone.0174876.
220. Obál F, Kapás L, Gardi J, Taishi P, Bodosi B, Krueger JM. Insulin-like growth factor-1 (IGF-1)-induced inhibition of growth hormone secretion is associated with sleep suppression. Brain Res. 1999;818(2):267-74.
221. Chennaoui M, Drogou C, Sauvet F, Gomez-merino D, Scofield DE, Nindl BC. Effect of acute sleep deprivation and recovery on Insulin-like Growth Factor-I responses and inflammatory gene expression in healthy men. Eur Cytokine Netw. 2014;25(3):52-7.
222. Rasmussen MH, Wildschiødtz G, Juul A, Hilsted J. Polysomnographic sleep, growth hormone insulin-like growth factor-I axis, leptin, and weight loss. Obesity (Silver Spring). 2008;16(7):1516-21.
223. Levada OA, Troyan AS. Insulin-like growth factor-1: a possible marker for emotional and cognitive disturbances, and treatment effectiveness in major depressive disorder. Annals of General Psychiatry. 2017;16:38. doi:10.1186/s12991-017-0161-3.
224. Peterfi Z, McGinty D, Sarai E, Szymusiak R. Growth hormone-releasing hormone activates sleep regulatory neurons of the rat preoptic hypothalamus. American Journal of Physiology – Regulatory, Integrative and Comparative Physiology. 2010;298(1):R147-R156. doi:10.1152/ajpregu.00494.2009.