GHRH(1-29) Receptor Agonist (Growth-Hormone Secretagogue, GRF Class)

Sermorelin

Also Known As: Geref, GRF(1-29), GRF(1-29)NH₂, GHRH(1-29), GHRH(1-29)NH₂, sermorelin acetate

Sermorelin is a synthetic 29-amino-acid peptide corresponding to residues 1–29 of human growth-hormone-releasing hormone (GHRH/GRF(1-44)) with a C-terminal amide. It is the shortest GHRH fragment that retains the full biological activity of the parent peptide at the pituitary GHRH receptor (GHRHR), eliciting endogenous, pulsatile growth-hormone release from somatotrophs. The compound was approved by the FDA on 7 October 1997 as Geref® (NDA 20-443) for pediatric growth-hormone deficiency; manufacturer EMD Serono voluntarily discontinued the product in December 2008 — the FDA explicitly determined the withdrawal was for commercial / manufacturing reasons, not safety or effectiveness (Federal Register 78 FR 14122, 4 March 2013). There is currently no FDA-approved sermorelin product on the US market; supply is primarily via 503A/503B compounding pharmacies, which is not equivalent to FDA approval.

Identity & Chemistry

Two-dimensional structural formula of sermorelin, the 29-amino-acid C-terminally amidated peptide GRF(1-29)NH₂ corresponding to residues 1–29 of human growth hormone-releasing hormone.
Image credit: Innerstream, via Wikimedia Commons · Public Domain
Amino Acid Sequence
YADAIFTNSYRKVLGQLSARKLLQDIMSR-NH₂
Molecular Formula
C₁₄₉H₂₄₆N₄₄O₄₂S
Molecular Weight
3357.93 Da
CAS Number
86168-78-7
PubChem CID
16132413
DrugBank ID
DB00010
IUPAC Name
L-Tyrosyl-L-alanyl-L-α-aspartyl-L-alanyl-L-isoleucyl-L-phenylalanyl-L-threonyl-L-asparaginyl-L-seryl-L-tyrosyl-L-arginyl-L-lysyl-L-valyl-L-leucyl-glycyl-L-glutaminyl-L-leucyl-L-seryl-L-alanyl-L-arginyl-L-lysyl-L-leucyl-L-leucyl-L-glutaminyl-L-α-aspartyl-L-isoleucyl-L-methionyl-L-seryl-L-argininamide
Solubility
Water-soluble; lyophilised sermorelin acetate is reconstituted clinically with bacteriostatic or sterile water for subcutaneous administration.
Storage
Lyophilised powder: store at −20 °C protected from light. Reconstituted solution: store at 2–8 °C; short-term stability per pharmacy reconstitution standards. Avoid freeze-thaw cycles.

Mechanism of Action

Sermorelin is a synthetic analogue of residues 1–29 of human GHRH that activates the GHRHR on pituitary somatotrophs to evoke physiologic, pulsatile release of endogenous growth hormone (GH) while preserving negative feedback by somatostatin and IGF-1.

Sermorelin (GRF(1-29)NH₂) corresponds to the N-terminal 29 residues of the 44-residue native human GHRH and is the shortest fragment that retains the full intrinsic agonist activity of the parent molecule (Prakash & Goa, BioDrugs 1999). After subcutaneous administration, peak plasma concentrations occur within ~5–20 minutes, but the peptide is rapidly inactivated in plasma — predominantly by dipeptidyl peptidase-IV (DPP-IV), which cleaves the N-terminal Tyr-Ala dipeptide to yield the inactive GRF(3-29)NH₂ — giving an elimination half-life of roughly 11–12 minutes. Despite this brief residence, transient GHRHR engagement is sufficient to trigger a discrete GH pulse with a pharmacodynamic effect lasting 1–2 hours. Because the stimulus is pulsatile and the response remains under endogenous IGF-1 and somatostatin feedback, sermorelin is mechanistically distinct from exogenous recombinant human growth hormone (somatropin), which directly raises systemic GH without preserving pulsatility, and from longer-acting GHRH analogues such as tesamorelin (a stabilised GHRH(1-44) with N-terminal trans-3-hexenoyl protection) and CJC-1295 (a DPP-IV-resistant GHRH(1-29) with optional drug-affinity-complex / DAC conjugation that extends half-life from minutes to days).

Molecular Targets

  • GHRH receptor (GHRHR; UniProt Q02643) — class B G-protein-coupled receptor on anterior-pituitary somatotrophs; primary target of sermorelin
  • Growth-hormone axis (pituitary → liver) — secondary increase in endogenous GH and downstream hepatic IGF-1
  • No meaningful agonism at the ghrelin / GHS-R1a receptor (mechanistically distinct from GHRP-class secretagogues such as ipamorelin or GHRP-2/-6)

Signaling Pathways

  • GHRHR → Gαs → adenylyl cyclase → ↑ cAMP → PKA → CREB phosphorylation → upregulation of the GH1 gene and exocytotic GH release from secretory granules
  • Secondary phospholipase-C / IP₃ / DAG arm modulates Ca²⁺ influx and somatotroph proliferation
  • GH → hepatic GH receptor → JAK2/STAT5b → IGF-1 transcription and systemic anabolic / metabolic effects
  • Physiologic feedback by IGF-1 and somatostatin is preserved — pulsatile rather than supraphysiologic GH profiles

Research Applications

Sermorelin was studied in a pivotal pediatric Phase III programme (Thorner et al., JCEM 1996, the basis of the 1997 Geref approval), in a comprehensive BioDrugs review (Prakash & Goa 1999), and in small Phase II trials in older adults (Khorram 1997; Vittone 1997). The modern adult evidence base is limited and largely restricted to surrogate endpoints.

Pediatric growth-hormone deficiency (pivotal Phase III; n = 110, 86 evaluable)

Phase III

Studies report that 30 µg/kg subcutaneous sermorelin once nightly for up to 12 months raised mean height velocity from 4.1 ± 0.9 cm/yr at baseline to 8.0 ± 1.5 cm/yr at 6 months and 7.2 ± 1.3 cm/yr at 12 months, with ~74% of participants classed as good responders at 6 months. Bone-age progression remained proportional to height gains, with no adverse changes in glucose or IGF-1 generation.

— Thorner et al., J Clin Endocrinol Metab 1996;81(3):1189–1196

Diagnostic stimulation testing of pituitary GH reserve

Phase II

Pharmacological diagnostic use: studies report that intravenous sermorelin at 1 µg/kg reliably evokes a measurable GH peak in subjects with intact somatotroph function and produces fewer false positives than several alternative provocative tests (e.g. insulin tolerance, arginine), but cannot, on its own, distinguish a hypothalamic from a pituitary origin of GH deficiency.

— Prakash & Goa, BioDrugs 1999;12(2):139–157

Endocrine and body-composition effects in older adults (RCT, n = 19, 16 weeks)

Phase II

Studies report that nightly subcutaneous GHRH(1-29) analogue 10 µg/kg produced significant rises in nocturnal integrated GH, serum IGF-1 (P < 0.05) and IGFBP-3 (P < 0.001) within 2 weeks; significant increases in skin thickness in both sexes and in lean body mass in men only (+1.26 kg, P < 0.05) with improved insulin sensitivity in men. No change in bone mineral density.

— Khorram et al., J Clin Endocrinol Metab 1997;82(5):1472–1479

PK/PD pilot in healthy elderly men (n = 11, 6 weeks)

Phase I

Studies report that 2 mg subcutaneous sermorelin nightly produced reproducible nocturnal GH and IGF-1 rises but only a modest body-composition signal in this short, single-arm study. The adult evidence base is small and >25 years old; off-label / anti-aging marketing claims are not validated by Triscience editorial.

— Vittone et al., Metabolism 1997;46(1):89–96

Clinical Status

Regulatory Status
Historically approved in the United States as Geref® (NDA 20-443) on 7 October 1997 for pediatric growth-hormone deficiency; previously approved (1990) as a diagnostic agent under NDA 19-863. EMD Serono notified the FDA by letter dated 2 December 2008 that Geref injection was being discontinued; the FDA explicitly determined in Federal Register 78 FR 14122 (4 March 2013) that the withdrawal was for commercial / manufacturing reasons — not for reasons of safety or effectiveness. There is currently no FDA-approved sermorelin product on the US market; supply is primarily via 503A/503B compounding pharmacies, which is not equivalent to FDA approval. No active EU marketing authorisation by the EMA is publicly listed.
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Highest Trial Phase
Phase III (pediatric Geref registration programme); adult studies are Phase I–II in scale (small, short, surrogate-based)
Sponsor
Originator Serono → EMD Serono (US subsidiary; now part of Merck KGaA); historical GHRH characterisation by Guillemin/Rivier and Ling/Esch in the early 1980s

Safety Profile

Observed in research settings

In published trials sermorelin was generally well tolerated in research settings; the most frequent events were mild, transient, and local — predominantly injection-site reactions and facial flushing. Anti-sermorelin antibodies were observed in a minority of pediatric long-term users without consistently impairing efficacy. Long-term safety data in healthy adults are insufficient.

Adverse Events Reported in Studies

  • Injection-site reactions (pain, redness, swelling, induration)
  • Transient facial flushing
  • Headache
  • Dysgeusia (altered taste), nausea, vomiting (more often with intravenous diagnostic dosing)
  • Pallor, dizziness (uncommon)

Serious Adverse Events

  • Anti-sermorelin antibodies in a subset of pediatric patients on chronic dosing — published series report no consistent impairment of growth response
  • Rare hypersensitivity reactions
  • Theoretical concern with chronic non-indicated adult use: sustained IGF-1 elevation has been epidemiologically associated with risk signals across the GH/IGF-1 axis (e.g. neoplasia, insulin resistance); specific long-term safety data for sermorelin in healthy adults are insufficient

References

  1. Thorner M, Rochiccioli P, Colle M, Lanes R, Grunt J, Galazka A, Landy H, Eengrand P, Shah S; Geref International Study Group 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 1996;81(3):1189–1196. 1996 .

    DOI: 10.1210/jcem.81.3.8772599 PMID: 8772599 View Source

  2. Prakash A, Goa KL Sermorelin: a review of its use in the diagnosis and treatment of children with idiopathic growth hormone deficiency. BioDrugs 1999;12(2):139–157. 1999 .

    DOI: 10.2165/00063030-199912020-00007 PMID: 18031173 View Source

  3. 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):1472–1479. 1997 .

    DOI: 10.1210/jcem.82.5.3943 PMID: 9141536 View Source

  4. Vittone J, Blackman MR, Busby-Whitehead J, Tsiao C, Stewart K, Tobin J, Stevens T, Bellantoni MF, Rogers MA, Baumann G, Roth J, Harman SM, Spencer RGS Effects of single nightly injections of growth hormone-releasing hormone (GHRH 1-29) in healthy elderly men. Metabolism 1997;46(1):89–96. 1997 .

    DOI: 10.1016/S0026-0495(97)90174-8 PMID: 9005976 View Source

  5. Walker RF Sermorelin: a better approach to management of adult-onset growth hormone insufficiency? Clin Interv Aging 2006;1(4):307–308. 2006 .

    DOI: 10.2147/ciia.2006.1.4.307 PMID: 18046908 View Source

  6. Bongers J, Lambros T, Ahmad M, Heimer EP Kinetics of dipeptidyl peptidase IV proteolysis of growth hormone-releasing factor and analogs. Biochim Biophys Acta 1992;1122(2):147–153. 1992 .

    PMID: 8358376 View Source

  7. U.S. Food and Drug Administration Determination That GEREF (Sermorelin Acetate) Injection, 0.5 Milligrams Base/Vial and 1.0 Milligrams Base/Vial, Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness. Federal Register 78(42):14122 (4 March 2013). 2013 .

    View Source

Frequently Asked Questions

What is sermorelin?
Sermorelin is a synthetic 29-amino-acid peptide corresponding to residues 1–29 of human growth-hormone-releasing hormone (GHRH), with a C-terminal amide. It is the shortest GHRH fragment that retains full biological activity at the GHRH receptor and was approved by the FDA in 1997, under the brand name Geref®, for treating pediatric growth-hormone deficiency before being voluntarily withdrawn from the US market in 2008 for commercial reasons.
How does sermorelin differ from rhGH (somatropin)?
Recombinant human growth hormone (somatropin) is GH itself, administered exogenously, which directly raises systemic GH levels in a sustained (non-pulsatile) fashion that does not respect normal feedback. Sermorelin instead stimulates the patient’s own pituitary somatotrophs via the GHRH receptor, eliciting pulsatile, physiologic GH release that remains under endogenous somatostatin and IGF-1 feedback (Walker, Clin Interv Aging 2006).
How does sermorelin differ from tesamorelin or CJC-1295?
All three are GHRH receptor agonists, but they differ in pharmacokinetics. Sermorelin is unmodified GHRH(1-29) with a half-life of ~11–12 minutes due to rapid DPP-IV cleavage. Tesamorelin is a stabilised GHRH(1-44) analogue with an N-terminal trans-3-hexenoyl group that resists DPP-IV degradation and is FDA-approved for HIV-associated lipodystrophy. CJC-1295 is a DPP-IV-resistant GHRH(1-29) variant; with the optional drug-affinity-complex (DAC) modification it covalently binds serum albumin and extends half-life from minutes to days.
Is sermorelin approved?
Sermorelin was FDA-approved as Geref® in 1997 for pediatric GH deficiency (NDA 20-443), but EMD Serono voluntarily discontinued the product on 2 December 2008. The FDA explicitly determined the withdrawal was for commercial / manufacturing reasons, not safety or effectiveness (Federal Register 78 FR 14122). There is currently no FDA-approved sermorelin product on the US market; supply is via compounding pharmacies, which is not equivalent to FDA approval. No central EMA marketing authorisation in the EU is publicly listed.
What is the molecular structure of sermorelin?
Sermorelin is a linear 29-residue peptide with the sequence YADAIFTNSYRKVLGQLSARKLLQDIMSR-NH₂ (C-terminal amide), molecular formula C₁₄₉H₂₄₆N₄₄O₄₂S, and a molecular weight of 3357.93 Da (free base; CAS 86168-78-7). Research material is typically supplied as the acetate salt (CAS 114466-38-5); catalogue weights for the acetate are listed slightly higher (~3417.99 Da) depending on the stoichiometry of bound acetate.
What are the main side effects observed in sermorelin studies?
In published pediatric registration trials and adult diagnostic use, the most frequently reported adverse events have been mild and transient: injection-site pain, redness or swelling, facial flushing, headache, altered taste, and occasional nausea. Anti-sermorelin antibodies have been reported in a minority of pediatric long-term users without consistent impact on efficacy. Long-term safety data in healthy adults are limited.

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