Sermorelin (GHRH 1-29): What the Research Literature Covers

Research-use-only context. This article summarizes published third-party scientific literature and laboratory practice. It is not medical advice, not a therapeutic or performance claim, and not a usage guide. US Prime Peptides products are supplied strictly for in vitro laboratory research and are not for human or veterinary use.

This article explains what sermorelin is as a molecule, how the 29-residue fragment of growth hormone-releasing hormone was identified, what the cloned-receptor and pituitary-cell literature reports about how it signals, why it is short-lived in plasma, and what its approval and discontinuation history as Geref means for a research vial today.

Sermorelin is GHRH(1-29) with an amidated C-terminus

Sermorelin is the first 29 residues of human growth hormone-releasing hormone (GHRH), synthesized with a C-terminal amide: Tyr-Ala-Asp-Ala-Ile-Phe-Thr-Asn-Ser-Tyr-Arg-Lys-Val-Leu-Gly-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-Asp-Ile-Met-Ser-Arg-NH2. In the older literature it is written GRF(1-29)-NH2 or hpGRF-29, where GRF stands for growth hormone-releasing factor and hp for human pancreatic, a reference to where the native hormone was first isolated. Its formula is C149H246N44O42S and its molecular weight is about 3,357.9 Da; it is usually supplied as an acetate salt.

The native hormone exists in longer forms. Rivier, Spiess, Thorner and Vale characterized a 44-residue amidated peptide from a human pancreatic islet tumor in a 1982 Nature paper, and a 40-residue free-acid form was isolated from a different tumor the same year. The 1-29 fragment was adopted because it is the shortest sequence that retains the full receptor activity of the parent, a point made plainly in Prakash and Goa's 1999 BioDrugs review of sermorelin. Everything after residue 29 can be removed without loss of receptor engagement; everything before residue 29 cannot.

Sermorelin is the unmodified reference point for the engineered analogs covered elsewhere on this site: TH9507 keeps all 44 residues and adds an N-terminal acyl group, and CJC-1295 keeps the 29-residue frame and substitutes four positions.

The founding structure-activity work in rat pituitary cells

The most informative early paper on the 29-residue fragment is an in vitro study. Heiman, Nekola, Murphy, Lance and Coy, in a 1985 Endocrinology paper, described a primary culture of dispersed male rat anterior pituitary cells plated at 200,000 cells per well and stimulated for three hours with synthetic hpGRF-29 and its analogs, with secreted hormone measured by radioimmunoassay. The cells responded to hpGRF-29 at a minimum effective concentration of 0.4 femtomolar, which the authors called unprecedented, and the response was specific: no LH, FSH or prolactin release was seen, and bombesin and vasoactive intestinal peptide were inactive.

The same paper laid out the position-by-position rules that later analog designers used. Replacing L-alanine at position 2 with D-alanine made the fragment about fifty times more active in this system, a change that also blocks the enzyme described in the next section. Replacing threonine at position 7 with its D-isomer made the fragment about ten thousand times less active, marking position 7 as part of the receptor-contact face. In vitro potencies in this culture tracked the in vivo potencies reported for the same analogs, which is why the dispersed rat pituitary assay became the standard screen for the GHRH analog field.

Horvath, Groot and Schally extended the readout in a 1995 Proceedings of the National Academy of Sciences paper using superfused rat pituitary cells. Three-minute pulses of GHRH released both growth hormone and cAMP, but with very different half-maximal concentrations (0.21 nM for the hormone, 52.5 nM for cAMP), and somatostatin-14 blocked the hormone release without blocking the immediate cAMP discharge. Their conclusion, that a cAMP pulse alone cannot account for secretion and that other signaling steps participate, remains the standard caveat when GHRH analogs are described simply as cAMP agonists.

The receptor: a class B GPCR confined to the anterior pituitary

Sermorelin acts through the GHRH receptor, a class B G-protein-coupled receptor that Kelly Mayo cloned in a 1992 Molecular Endocrinology paper. Mayo amplified G-protein-coupled receptor sequences from rat pituitary mRNA, isolated the human homolog, and expressed it in HEK 293 cells, whose membranes then bound human GHRH with high affinity and specificity and responded with intracellular cAMP production. The receptor has seven membrane-spanning segments and is homologous to the secretin and VIP receptors, and the rat transcript was found predominantly, if not exclusively, in the anterior pituitary.

Genetics confirmed that this receptor is the relevant target. Godfrey and colleagues, in a 1993 Nature Genetics paper, mapped the receptor gene to mouse chromosome 6 in the region of the little mutation and identified a missense change in the extracellular domain of the little receptor that disrupts its function; homozygous mice have reduced growth hormone secretion.

The structural picture arrived with cryo-electron microscopy. Zhou and colleagues, in a 2020 Nature Communications paper, reported a 2.6-angstrom structure of the human GHRH receptor bound to its endogenous ligand and the stimulatory G protein. The alpha-helical peptide forms a continuous network of contacts involving all three extracellular loops, every transmembrane helix except TM4, and the receptor's extracellular domain, with the N-terminus of GHRH engaging a broad set of specific interactions. That last detail explains why the N-terminal residues matter so much in the analog literature: they are not a loose tail but a receptor-contact surface.

Why the 1-29 fragment is short-lived in plasma

Sermorelin is inactivated quickly in plasma because a single enzyme clips two residues off its N-terminus. Frohman, Downs, Heimer and Felix characterized the reaction in a 1989 Journal of Clinical Investigation paper: GHRH(1-44)-NH2, GHRH(1-40)-OH, GHRH(1-32)-NH2 and GHRH(1-29)-NH2 were all cleaved rapidly at the Ala2-Asp3 bond, the product was generated in one step rather than by sequential aminopeptidases, the reaction was blocked by diprotin A, and a D-amino acid at position 1 or 2 prevented it. Those properties identified the enzyme as dipeptidyl peptidase IV (DPP-IV). A slower trypsin-like cleavage near residues 11 to 13 was also seen. Because the structure work above shows the N-terminus in direct receptor contact, the (3-29) product is inactive.

Bongers and colleagues measured the kinetics with purified human placental DPP-IV in a 1992 Biochimica et Biophysica Acta paper, using HPLC to follow the Ala2-Asp3 cleavage. Initial rates were about 5 micromoles per minute per milligram of enzyme for GRF(1-44)-NH2, GRF(1-29)-NH2 and GRF(1-20)-NH2 alike, and analogs with D-configuration at the first two positions, or with the N-terminal amine removed or methylated, were not cleaved. The two obvious design responses, a D-alanine at position 2 or an acyl cap on the N-terminal amine, are exactly the moves taken by CJC-1295 and TH9507 respectively.

Enzymes are not the only concern. Campbell and colleagues, in a 1994 Peptides paper, catalogued two chemical routes by which the GHRH sequence loses activity in aqueous solution: asparagine 8 rearranges to aspartate or isoaspartate through an aminosuccinimide intermediate, and methionine 27 oxidizes to the sulfoxide. Both residues are present in sermorelin, which is why a reconstituted solution is far less stable than the lyophilized cake and why the handling notes in aliquots, freeze-thaw and oxidation apply to it directly.

Regulatory history: Geref, approved and then discontinued

Sermorelin acetate was approved by the FDA in the 1990s under the brand name Geref, in a diagnostic presentation and later for a pediatric indication, and the product was discontinued in 2008. The discontinuation was a commercial decision by the marketing company; the product was not withdrawn for reasons of safety or effectiveness. Prakash and Goa's 1999 BioDrugs review documents the clinical record of that period, including its use as a provocative test of pituitary growth hormone reserve and the fact that a normal response to sermorelin cannot exclude a hypothalamic cause of deficiency.

Two consequences follow for a research buyer. First, no finished drug product containing sermorelin is currently approved and marketed in the United States, so any vial labeled sermorelin is either a compounded preparation made under a pharmacy framework or a research-grade chemical. A research vial from US Prime Peptides is the latter: it is not Geref, it is not a compounded drug, and it is supplied strictly for in vitro work. Second, GHRH and its synthetic analogs, sermorelin included, are listed under section S2 of the World Anti-Doping Agency Prohibited List. Memdouh and colleagues, in a 2021 Drug Testing and Analysis paper, developed a liquid chromatography-tandem mass spectrometry method for sermorelin, TH9507 and both forms of CJC-1295 in urine, synthesizing nineteen in vitro metabolites as reference materials, including sermorelin(3-29)-NH2, the DPP-IV product, and reaching detection limits of about 1 ng/mL. The same analytical chemistry that anti-doping laboratories use is the chemistry a certificate of analysis relies on.

What a certificate should show for sermorelin

A sermorelin certificate should confirm identity by mass spectrometry, report purity by HPLC as area percent, and state the net peptide content, because a 29-residue peptide with four arginines and two lysines carries a substantial counter-ion load. The expected monoisotopic mass of the free peptide is about 3,355.8 Da (average 3,357.9), which electrospray instruments usually report as the triply and quadruply charged ions near m/z 1,119 and 840. The two degradation routes described above have mass signatures worth knowing: methionine 27 oxidation adds 16 Da and typically elutes slightly earlier on reverse-phase HPLC, while asparagine 8 deamidation adds only 1 Da and is easier to see as a split or shoulder on the main peak than in the mass spectrum. The chromatogram-reading notes in how to read an HPLC chromatogram cover both.

Endotoxin by LAL, sterility, and heavy metals by ICP-MS complete the standard panel, and the certificate should be lot-matched to the vial label. US Prime Peptides posts the independent third-party certificate for Sermorelin 5 mg and Sermorelin 10 mg on each product page before purchase; both are lyophilized powders synthesized and lyophilized in the USA.

Frequently Asked Questions

What is sermorelin?

Sermorelin is a synthetic peptide consisting of the first 29 amino acids of human growth hormone-releasing hormone with an amidated C-terminus, GHRH(1-29)-NH2. It is the shortest GHRH fragment that retains full activity at the GHRH receptor in pituitary-cell assays, with a molecular weight of about 3,358 Da.

Is sermorelin approved by the FDA?

Sermorelin acetate was approved by the FDA as Geref in the 1990s, and the product was discontinued in 2008 for commercial reasons rather than being withdrawn for safety or effectiveness. No approved sermorelin product is currently marketed, and a research vial is not Geref.

What receptor does sermorelin bind?

Sermorelin binds the GHRH receptor, a class B G-protein-coupled receptor cloned by Mayo in 1992 and expressed almost exclusively in the anterior pituitary. The 2020 cryo-EM structure shows the peptide's N-terminus making extensive contacts with the receptor, which is why N-terminal cleavage inactivates it.

Why does sermorelin degrade so quickly in plasma?

Dipeptidyl peptidase IV cleaves the Ala2-Asp3 bond, removing the first two residues and producing inactive GHRH(3-29). The 1989 Frohman study and the 1992 Bongers kinetics paper characterized this reaction, and later analogs such as CJC-1295 and TH9507 were designed specifically to block it.

Citations

1. Rivier J, Spiess J, Thorner M, Vale W. Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour. Nature. 1982;300:276-278. PMID 6292724
2. 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. 1985;116:410-415. PMID 2856874
3. Frohman LA, Downs TR, Heimer EP, Felix AM. Dipeptidylpeptidase IV and trypsin-like enzymatic degradation of human growth hormone-releasing hormone in plasma. J Clin Invest. 1989;83:1533-1540. PMID 2565342
4. 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;1122:147-153. PMID 1353684
5. Mayo KE. Molecular cloning and expression of a pituitary-specific receptor for growth hormone-releasing hormone. Mol Endocrinol. 1992;6:1734-1744. PMID 1333056
6. Godfrey P, Rahal JO, Beamer WG, et al. GHRH receptor of little mice contains a missense mutation in the extracellular domain that disrupts receptor function. Nat Genet. 1993;4:227-232. PMID 8395283
7. Campbell RM, Stricker P, Miller R, et al. Enhanced stability and potency of novel growth hormone-releasing factor (GRF) analogues derived from rodent and human GRF sequences. Peptides. 1994;15:489-495. PMID 7937325
8. Horvath JE, Groot K, Schally AV. Growth hormone-releasing hormone stimulates cAMP release in superfused rat pituitary cells. Proc Natl Acad Sci U S A. 1995;92:1856-1860. PMID 7892191
9. Prakash A, Goa KL. Sermorelin: a review of its use in the diagnosis and treatment of children with idiopathic growth hormone deficiency. BioDrugs. 1999;12:139-157. PMID 18031173
10. Zhou F, Zhang H, Cong Z, et al. Structural basis for activation of the growth hormone-releasing hormone receptor. Nat Commun. 2020;11:5205. PMID 33060564
11. Memdouh S, Gavrilovic I, Ng K, et al. Advances in the detection of growth hormone releasing hormone synthetic analogs. Drug Test Anal. 2021;13:1871-1887. PMID 34665524

This article is for laboratory research reference only. US Prime Peptides products are supplied strictly for in vitro research. Not for human consumption.

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