Sermorelin: Mechanism of Action
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1. Receptor Target — GHRH Receptor
Sermorelin binds specifically to the GHRH receptor (GHRHR) on somatotroph cells in the anterior pituitary gland. Despite being a 29-aa fragment, it is equipotent to full-length GHRH(1-40) in stimulating GH secretion. [1] [6]
2. Downstream Signaling Cascades
Upon binding to the GHRHR, Sermorelin activates multiple intracellular pathways:
- Gₛ/Adenylyl Cyclase → cAMP Pathway: Primary mechanism — receptor activation triggers Gₛα, stimulating adenylyl cyclase to produce cAMP as a second messenger [6]
- MAPK Pathway: GHRHR activation also stimulates the mitogen-activated protein kinase pathway [6]
- Ca²⁺ Signaling: Cascades raise intracellular calcium levels, facilitating vesicle fusion and exocytosis of growth hormone
🔑 Pulsatile GH Release: Unlike exogenous rhGH, Sermorelin stimulates the pituitary to release GH in natural bursts/pulses, mimicking neuroendocrine rhythms and avoiding tachyphylaxis. Its action is regulated by somatostatin negative feedback, making overdose difficult. [3]
The product supplied here is for research use only regardless of regulatory status of related formulations.
3. Dose-Response Characteristics
- Duration vs Peak: The duration of GH release is more dose-dependent than peak magnitude [6]
- Elderly Restoration: High-dose Sermorelin (1 mg BID) restores IGF-1 in elderly men to young adult levels [7]
- In Vitro Sensitivity: Minimal effective dose in rat pituitary cultures: 0.4 × 10⁻¹⁵ M [8]
4. Receptor Selectivity
In vitro: Does NOT stimulate LH, FSH, or Prolactin release (high somatotroph selectivity). [8]
In vivo (human): Minor acute rises in prolactin, FSH, and LH reported in children — effect not seen with GHRH(1-40) — suggesting slight differences between fragment and full-length. [9]
5. Cellular and Tissue-Level Effects
Anti-Tumor (Glioma):
- Blocks cell cycle progression in recurrent glioma cells
- Negatively regulates immune checkpoints, downregulates GHRHR/GGF
- Identified as most effective candidate from 4,865 drugs (P<0.0001) [10]
Immune Activation:
- Increases B cell number (~30%) and responsiveness to mitogens (+50%)
- Increases lymphocytes expressing IL-2 receptors (+70%)
- Enhances T cell responsiveness to phytohemagglutinin (+50%) [11]
6. Comparison to Related Compounds
| Compound | Structure | Key Difference |
|---|---|---|
| Sermorelin | 29 aa (native fragment) | Shortest functional GHRH; T½ ~11 min; equipotent to 1-40 |
| Tesamorelin | 44 aa + hexenoyl cap | DPP-4 resistant; T½ ~30 min; more potent |
| D-Ala²-GHRH(1-29) | 29 aa + D-Ala² | Lower clearance; longer T½ than native fragment |
| CJC-1295 + DAC | GHRH analog + DAC | Days-long T½ via albumin binding; continuous GH |
| Somatropin (rhGH) | Exogenous GH | Bypasses pituitary; constant levels; higher risk |
7. Pharmacokinetics
| Parameter | Value |
|---|---|
| Route | SC (experimental), IV (diagnostic) |
| Bioavailability | ~6% (SC); ~5.1% in rats |
| Half-Life (T½) | ~11–12 min (SC/IV); ~6.2 min in rats |
| Tmax | 5–20 min (SC) |
| Clearance | 2.4–2.8 L/min (adults) |
| GH Pulsatility | Preserved (natural pulses, somatostatin feedback intact) |
| Metabolism | DPP-4 proteolysis; no N-terminal modification |
References
- Chang Y, Huang R, Zhai Y, et al. A potentially effective compound for study subjects with recurrent glioma: sermorelin. Ann Transl Med, 9(5), 406, 2021.
- Prakash A, Goa KL. Sermorelin: a review of its use in the diagnosis and investigation of children with idiopathic growth hormone deficiency. BioDrugs, 12(2), 139-157, 1999.
- Walker RF. Sermorelin: a better approach to management of adult-onset growth hormone insufficiency? Clin Interv Aging, 1(4), 307-308, 2006.
- Food and Drug Administration. Determination That GEREF (Sermorelin Acetate) Injection Was Not Withdrawn From Sale for Reasons of tolerability or Effectiveness. Fed Register, 78(42), 14095-14096, 2013.
- Sinha DK, Balasubramanian A, Tatem AJ, et al. Beyond the androgen receptor: the role of growth hormone secretagogues in the modern management of body composition in hypogonadal males. Transl Androl Urol, 9(Suppl 2), S149-S159, 2020.
- Grossman AB, Savage MO, Lytras N, Besser GM. Responses to analogues of growth hormone releasing hormone in normals and in GH-deficient children and young adults. Clin Endocrinol (Oxf), 21(3), 321-330, 1984.
- Corpas E, Harman SM, Piñeyro MA, et al. Growth hormone (GH)-releasing hormone-(1-29) twice daily reverses the decreased GH and insulinlike growth factor-I levels in old men. J Clin Endocrinol Metab, 75(2), 530-535, 1992.
- Heiman ML, Nekola MV, Murphy WA, Lance VA, Coy DH. An extremely sensitive in vitro model for elucidating structure-activity relationships of growth hormone-releasing factor analogs. Endocrinology, 116(1), 410-415, 1985.
- Gelander L, Lindstedt G, Selstam G, et al. Effects of acute IV injection of two growth hormone-releasing hormones on serum GH and other pituitary hormones in short children. Horm Res, 31(5-6), 213-220, 1989.
- Khorram O, Laughlin GA, Yen SS. Endocrine and metabolic effects of long-term administration of [Nle27]GHRH-(1-29)-NH2 in age-advanced men and women. J Clin Endocrinol Metab, 82(5), 1472-1479, 1997.
- Khorram O, Yeung M, Vu L, Yen SS. Effects of [norleucine27]growth hormone-releasing hormone (GHRH) (1-29)-NH2 administration on the immune system of aging men and women. J Clin Endocrinol Metab, 82(11), 3590-3596, 1997.
- Vittone J, Blackman MR, Busby-Whitehead J, et al. Effects of single nightly injections of GHRH 1-29 in healthy elderly men. Metabolism, 46(1), 89-96, 1997.
- Vitiello MV, Schwartz RS, Moe KE, Mazzoni G, Merriam GR. Treating age-related changes in somatotrophic hormones, sleep, and cognition. Dialogues Clin Neurosci, 3(3), 229-236, 2001.
- Sigalos JT, Pastuszak AW, Allison A, et al. Growth Hormone Secretagogue research application in Hypogonadal Men Raises Serum IGF-1 Levels. Am J Mens Health, 11(6), 1752-1757, 2017.
- Schally AV, Wang H, He J, et al. Agonists of growth hormone-releasing hormone (GHRH) inhibit human experimental cancers in vivo by down-regulating receptors for GHRH. PNAS, 115(47), 12028-12033, 2018.
- Jaszberenyi M, Rick FG, Popovics P, et al. Potentiation of cytotoxic chemotherapy by growth hormone-releasing hormone agonists. PNAS, 111(2), 781-786, 2014.
- Soule SG, King JA, Millar RP. Incorporation of D-Ala2 in GHRH-(1-29)-NH2 increases half-life and decreases metabolic clearance in normal men. J Clin Endocrinol Metab, 79(4), 1208-1211, 1994.
- Merriam GR, Buchner DM, Prinz PN, Schwartz RS, Vitiello MV. Potential applications of GH secretagogs in the evaluation and investigation of the age-related decline in GH secretion. Endocrine, 7(1), 49-52, 1997.
- Walker RF, Yang SW, Bercu BB. Robust Growth Hormone (GH) secretion in aged female rats co-administered GH-releasing hexapeptide (GHRP-6) and GH-releasing hormone (GHRH). Life Sci, 49(20), 1499-1504, 1991.
- Rafferty B, Coy DH, Poole S. Pharmacokinetic evaluation of superactive analogues of growth hormone-releasing factor (1-29)-amide. Peptides, 9(1), 207-209, 1988.
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