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Sermorelin (5 mg)
Sermorelin (GHRH(1-29)-NH₂) is a 29-amino acid synthetic fragment of human growth hormone-releasing hormone with C-terminal amidation. FDA-approved (1991 diagnostic, 1997 therapeutic), it activates pituitary GHRH-R via Gs-cAMP-PKA signaling while preserving physiological pulsatile GH secretion and somatostatin feedback regulation.
- Mechanistic pathway studies
- In vitro receptor profiling
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Research Overview
Sermorelin (GHRH(1-29)-NH₂) is a 29-amino acid synthetic peptide representing the biologically active N-terminal fragment of human growth hormone-releasing hormone. FDA-approved in 1991 (diagnostic) and 1997 (therapeutic) for GH deficiency; commercial product (Geref) discontinued 2008 due to manufacturing issues unrelated to safety. Retains complete GHRH-R binding affinity and biological activity with improved pharmaceutical characteristics. C-terminal amidation (-NH₂) at Arg29 provides carboxypeptidase protection; plasma half-life ~11-12 minutes, subcutaneous bioavailability ~6%. Activates pituitary GHRH-R (class B GPCR) → Gs-cAMP-PKA-CREB transcriptional cascade → upregulates GH gene transcription and Pit-1 auto-amplification loop. Triggers calcium mobilization via voltage-gated Ca²⁺ channels and PLC-IP3 signaling → rapid GH exocytosis. Preserves physiological pulsatile GH secretion via somatostatin and IGF-1 negative feedback, preventing supraphysiological GH levels (unlike rhGH). Clinical trials: Thorner 1996 (JCEM) - 8.0 cm/yr height velocity, 74% response rate in GH-deficient children (n=86). Khorram 1997 (JCEM) - increased nocturnal GH, IGF-1, IGFBP-3, skin thickness, lean body mass in adults 55-71 (16 weeks). Friedman 2013 (JAMA Neurology) - increased brain GABA levels in MCI and healthy aging (n=30, 20 weeks). Chang 2021 (Ann Transl Med) - top candidate from 4,865 FDA-approved drugs for recurrent gliomas via transcriptome screening (n=1,018 patients).
Mechanism of Action
Sermorelin exerts effects through multiple mechanisms: (1) GHRH-R Activation - highly specific binding to growth hormone-releasing hormone receptor (class B GPCR) on anterior pituitary somatotroph cells activates associated heterotrimeric Gs protein complex, stimulates adenylyl cyclase, elevates intracellular cAMP; (2) cAMP-PKA-CREB Transcriptional Cascade - elevated cAMP binds PKA regulatory subunits causing dissociation and activation of catalytic subunits, which translocate to nucleus and phosphorylate CREB transcription factor; phosphorylated CREB with coactivators p300/CBP enhances GH gene transcription via cAMP-response elements (CREs), upregulates GH mRNA levels, replenishes cellular GH stores; upregulates pituitary-specific Pit-1 transcription factor in auto-amplification loop (Pit-1 transcriptionally activates GH1, GHRHR, and Pit-1 genes); (3) Calcium-Dependent GH Exocytosis - cAMP-mediated opening of voltage-gated Ca²⁺ channels permits extracellular calcium influx triggering fusion of GH-containing secretory granules with plasma membrane; GHRH-R activation stimulates phospholipase C (PLC) generating IP3, which induces Ca²⁺ release from endoplasmic reticulum stores, further elevating cytosolic calcium; acute rapid GH release occurs within minutes; (4) Preserved Pulsatile GH Release - sermorelin-induced GH secretion is regulated by negative feedback through hypothalamic somatostatin (secreted in alternation with endogenous GHRH), making it "difficult if not impossible to achieve supraphysiological GH levels"; released GH stimulates hepatic IGF-1 production, which exerts further negative feedback on hypothalamic GHRH secretion and pituitary GH release; preserves episodic (pulsatile) GH pattern, avoids non-physiological "square wave" pharmacokinetics of rhGH injection, reduces tachyphylaxis risk; (5) Additional Pathways - MAPK/ERK pathway contributes to somatotroph proliferation and differentiation; PI3K/Akt pathway supports cell survival and metabolic responses; chronic trophic effects on somatotroph cell number and pituitary reserve capacity; (6) Structural Basis - N-terminal Tyr1 critical for receptor binding/activation (truncation abolishes activity); hydrophobic core (Ile5, Phe6, Tyr10) contributes to amphipathic alpha-helical structure for receptor recognition; C-terminal amidation (-NH₂) at Arg29 protects against carboxypeptidase degradation, extends plasma half-life to ~11-12 minutes.
“Mechanistic summaries on this page are provided for laboratory reference and should be interpreted within controlled experimental settings only.”
Preclinical Research Summary
Thorner et al. (1996, JCEM): multicenter open-label trial in 110 prepubertal GH-deficient children (86 eligible for efficacy analysis); daily subcutaneous GHRH(1-29) at 30 mcg/kg at bedtime for up to one year; mean height velocity increased from 4.1±0.9 cm/yr baseline to 8.0±1.5 cm/yr (6 months) and 7.2±1.3 cm/yr (12 months); 74% favorable treatment response at six months; bone age progression proportional to height gain. Khorram et al. (1997, JCEM): single-blind, randomized, placebo-controlled trial in 19 participants aged 55-71 years, treated nightly for 16 weeks; GHRH analog induced significant increases in nocturnal GH levels in both genders; elevated serum IGF-1 and IGFBP-3 within 2 weeks; significant increase in skin thickness in both genders; increased lean body mass and improved insulin sensitivity in men; transient hyperlipidemia was only adverse effect. Friedman et al. (2013, JAMA Neurology): randomized, double-blind, placebo-controlled trial in 30 adults (17 MCI, 13 cognitively normal) aged 55-87, treated with daily subcutaneous tesamorelin (GHRH analog) for 20 weeks; GABA levels increased in all brain regions (dorsolateral frontal, posterior cingulate, posterior parietal; P<0.04); myo-inositol decreased in posterior cingulate (P=0.002); first evidence that somatotropic supplementation modulates inhibitory neurotransmitter levels; favorable cognitive improvements paralleled neurochemical changes. Chang et al. (2021, Ann Transl Med): high-throughput screening of 4,865 FDA-approved drugs using CGGA transcriptome data from 1,018 glioma patients; sermorelin had lowest p-value and maximum difference value for recurrent vs. primary gliomas, suggesting therapeutic potential. Pharmacokinetics: plasma half-life ~11-12 minutes (IV or SC), clearance 2.4-2.8 L/min in adults, mean absolute subcutaneous bioavailability ~6%. Stability: lyophilized form stable 24+ months at -20°C to -80°C; reconstituted solutions stable 7-14 days at 2-8°C (pH 5.0-7.0). FDA approval: 1991 (diagnostic for GH deficiency assessment), 1997 (therapeutic for idiopathic GH deficiency in children); commercial product (Geref) voluntarily discontinued 2008 due to manufacturing difficulties unrelated to safety/efficacy.
Academic References
1. Thorner MO, et al. (1996). Once daily subcutaneous growth hormone-releasing hormone therapy accelerates growth in growth hormone-deficient children during the first year of therapy. J Clin Endocrinol Metab. 81(3):1189-1196. doi:10.1210/jcem.81.3.8772599 [Multicenter trial: 8.0 cm/yr height velocity, 74% response rate]
2. Khorram O, et al. (1997). 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. 82(5):1472-1479. doi:10.1210/jcem.82.5.3946 [16-week trial: increased GH, IGF-1, lean mass, skin thickness]
3. Friedman SD, et al. (2013). Growth Hormone-Releasing Hormone Effects on Brain gamma-Aminobutyric Acid Levels in Mild Cognitive Impairment and Healthy Aging. JAMA Neurology. 70(7):883-890. doi:10.1001/jamaneurol.2013.1425 [20-week trial: increased brain GABA in MCI and healthy aging]
4. Chang C, et al. (2021). A potentially effective drug for patients with recurrent glioma: sermorelin. Ann Transl Med. 9(5):406. doi:10.21037/atm-20-6987 [Transcriptome screening: top candidate from 4,865 drugs for recurrent gliomas]
5. Walker RF. (2006). Sermorelin: a better approach to management of adult-onset growth hormone insufficiency? Clin Interv Aging. 1(4):307-308. doi:10.2147/ciia.2006.1.4.307 [Mechanism review: preserves pulsatile GH, prevents supraphysiological levels]
6. Pombo M, et al. (2001). The growth hormone axis in pregnancy and lactation. Growth Horm IGF Res. 11 Suppl A:S35-38. doi:10.1016/s1096-6374(01)80007-0 [GHRH receptor signaling review]
7. Campbell RM, et al. (1996). Pharmacokinetics of GHRH and its analogs. J Pediatr Endocrinol Metab. 9 Suppl 3:333-338. doi:10.1515/jpem.1996.9.s3.333 [Pharmacokinetics: half-life 11-12 min, bioavailability ~6%]
8. Corpas E, et al. (1993). Human growth hormone and human aging. Endocr Rev. 14(1):20-39. doi:10.1210/edrv-14-1-20 [Age-related GH decline and somatopause mechanisms]
9. Mayo KE, et al. (2000). Regulation of the pituitary somatotroph cell by GHRH and its receptor. Recent Prog Horm Res. 55:237-266. [Comprehensive GHRH-R signal transduction review]
10. Giustina A, Veldhuis JD. (1998). Pathophysiology of the neuroregulation of growth hormone secretion in experimental animals and the human. Endocr Rev. 19(6):717-797. doi:10.1210/edrv.19.6.0353 [Somatostatin-GHRH feedback regulation]
This product is intended exclusively for in vitro laboratory research by qualified professionals. Not for human consumption. Not approved by the FDA.
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