Growth Hormone Secretagogues vs GHRH Analogues: A Classification Guide

Introduction

The phrase "growth hormone secretagogues" is applied in commerce to a mixed group of research peptides, and the grouping hides a basic pharmacological distinction. The eight compounds covered here belong to two separate receptor families that were discovered independently, share no sequence homology, and have followed different regulatory paths. One family consists of synthetic analogues of growth-hormone-releasing hormone (GHRH), a 44-residue hypothalamic hormone, acting at the GHRH receptor. The other consists of short synthetic peptides, historically called growth-hormone-releasing peptides (GHRPs), acting at the growth hormone secretagogue receptor subtype 1a (GHS-R1a), which was later identified as the receptor for the stomach hormone ghrelin.

This guide sorts each catalog compound into its receptor family, records sequence length and chemical modification as reported in the primary literature, and states the regulatory status of each as a matter of public record. It makes no statement about any compound's suitability for any purpose.

The two receptor families

The GHRH receptor

The GHRH lineage begins with the hormone itself. Guillemin and colleagues reported in Science in 1982 the isolation and sequencing of a growth-hormone-releasing factor from a human pancreatic tumor that had caused acromegaly, establishing the 44-residue sequence on which every later GHRH analogue is based [1]. Rivier, Spiess, Thorner, and Vale independently characterized a growth-hormone-releasing factor from a human pancreatic islet tumor in Nature the same year [2]. A decade later, Mayo reported the molecular cloning and expression of a pituitary-specific receptor for GHRH in Molecular Endocrinology [3]. The GHRH receptor is a class B G protein-coupled receptor expressed on anterior pituitary somatotroph cells; it was reported to signal through Gs and cyclic AMP.

Frohman and colleagues reported in the Journal of Clinical Investigation in 1989 that dipeptidyl peptidase IV and trypsin-like enzymes degraded GHRH in plasma [4]. Each GHRH analogue in the catalog is a different structural answer to that enzymatic problem.

The GHS-R1a ghrelin receptor

The second family developed in the opposite order: the synthetic ligands came first, and the receptor and its natural hormone were found afterward. Momany, Bowers, and colleagues reported in Endocrinology in 1981 on enkephalin-derived peptides that released growth hormone in vitro [5], and Bowers and colleagues reported in 1984 on a new synthetic hexapeptide, GHRP-6, that acted on the pituitary through a mechanism distinct from GHRH [6]. Howard and colleagues at Merck cloned the receptor responsible in Science in 1996 and named it the growth hormone secretagogue receptor [7]. Kojima and colleagues then identified its endogenous ligand, the acylated stomach peptide ghrelin, in Nature in 1999 [8]. GHS-R1a is a class A G protein-coupled receptor reported to couple primarily to Gq and phospholipase C.

Findings from research models do not establish safety or efficacy in humans. Sparta Labs makes no claims about the use of any compound discussed here.

GHS-R1a agonists: the growth-hormone-releasing peptides

The four peptidyl GHS-R1a agonists in the catalog are all five- or six-residue synthetic sequences with a C-terminal amide and at least two non-natural residues. None is derived from a natural hormone; Bowers reviewed the design lineage in Cellular and Molecular Life Sciences in 1998 [9].

GHRP-6

GHRP-6 is the class prototype: a hexapeptide with the sequence His-D-Trp-Ala-Trp-D-Phe-Lys-NH2 and a molecular weight of approximately 873 daltons [6]. It incorporates D-tryptophan at position 2 and D-phenylalanine at position 5, substitutions introduced in the Bowers program for resistance to proteolysis. GHRP-6 has never been developed toward marketing approval and is not an active ingredient in any approved drug product. Its relationship to the pentapeptide that followed it is examined in the GHRP-6 vs ipamorelin comparison.

GHRP-2 (pralmorelin)

GHRP-2 is a hexapeptide with the sequence D-Ala-D-2-Nal-Ala-Trp-D-Phe-Lys-NH2 and a free-base molecular weight of approximately 817 daltons. Its defining modification relative to GHRP-6 is D-2-naphthylalanine at position 2 in place of D-tryptophan, together with a D-alanine at position 1. Doi and colleagues published the preclinical pharmacological characterization of the compound, under the development code KP-102, in Arzneimittelforschung in 2004 [10]. Under the international nonproprietary name pralmorelin, GHRP-2 was approved in Japan in 2004 as a diagnostic agent for the assessment of growth hormone deficiency [11]. It is the only GHS-R1a agonist with a national regulatory approval, and it has not been approved by the FDA. Research-grade GHRP-2 is cataloged as a laboratory reference material.

Hexarelin

Hexarelin is a hexapeptide with the sequence His-D-2-Me-Trp-Ala-Trp-D-Phe-Lys-NH2 and a molecular weight of approximately 887 daltons. It differs from GHRP-6 by a single methyl group: D-2-methyltryptophan replaces D-tryptophan at position 2. Deghenghi and colleagues reported the compound's characterization in infant and adult rats in Life Sciences in 1994 [12]. Hexarelin has never been approved in any jurisdiction. Its structural relationship to the other position-2 variant is set out in the hexarelin vs GHRP-2 comparison.

Ipamorelin

Ipamorelin is the shortest member of the family, a pentapeptide with the sequence Aib-His-D-2-Nal-D-Phe-Lys-NH2 and a molecular weight of approximately 712 daltons. Raun and colleagues at Novo Nordisk reported in the European Journal of Endocrinology in 1998 that the compound emerged from a series lacking the central Ala-Trp dipeptide of the earlier hexapeptides, and that it carried an N-terminal alpha-aminoisobutyric acid (Aib) residue, a non-natural, conformationally restricted amino acid [13]. Ipamorelin was never submitted for marketing approval and holds no approval from the FDA or the European Medicines Agency. Research-grade ipamorelin is cataloged as a laboratory reference material.

GHRH analogues

The four GHRH analogues in the catalog share a common ancestor, the native 44-residue hormone, and are distinguished from one another by how much of that sequence they retain and by what chemistry has been added to slow enzymatic degradation.

Sermorelin

Sermorelin is GHRH(1-29)-NH2, the N-terminal 29-residue fragment of the native hormone with an amidated C-terminus and no other modification. Lance, Murphy, Sueiras-Diaz, and Coy reported in 1984 that this fragment retained full activity at the receptor, which is why later analogues were built on it [14]. Prakash and Goa reviewed the compound's clinical record in BioDrugs in 1999 [15]. Sermorelin acetate was approved by the FDA under the brand name Geref, in a diagnostic formulation and a formulation indicated for pediatric growth hormone deficiency; the products were later discontinued by their sponsor. In a March 2013 Federal Register notice the FDA determined that Geref was not withdrawn from sale for reasons of safety or effectiveness [16]. No sermorelin product is currently marketed under an FDA approval.

CJC-1295 without DAC (Modified GRF 1-29)

CJC-1295 without DAC is the sermorelin backbone with four amino-acid substitutions: D-Ala at position 2, Gln at position 8, Ala at position 15, and Leu at position 27. It remains 29 residues long, with a free-base molecular weight of approximately 3,367 daltons. Jetté and colleagues described this tetra-substituted scaffold, engineered for resistance to the cleavage Frohman had characterized, in Endocrinology in 2005 [17]. The compound has never been approved in any jurisdiction.

CJC-1295 with DAC

CJC-1295 with DAC carries the same four substitutions and adds a thirtieth residue: a C-terminal lysine bearing an N-epsilon-3-maleimidopropionamide group, the "drug affinity complex" (DAC). Jetté and colleagues reported that this maleimide forms a covalent bond with cysteine-34 of serum albumin, identifying CJC-1295 as a long-lasting GRF analogue [17]. The unconjugated peptide has a molecular formula of C165H269N47O46 and a molecular weight of approximately 3,647 daltons. Teichman and colleagues reported in the Journal of Clinical Endocrinology and Metabolism in 2006 an estimated half-life of 5.8 to 8.1 days in healthy adults [18]. An early-phase clinical program in the mid-2000s did not advance to approval, and the compound holds no approval anywhere. The single-group difference between the two variants is covered in the CJC-1295 DAC vs no DAC comparison; research-grade CJC-1295 with DAC is cataloged as a laboratory reference material.

Tesamorelin

Tesamorelin takes the opposite structural approach. It is the complete GHRH(1-44)-NH2 sequence, all 44 residues retained, with a single modification: a trans-3-hexenoyl group conjugated to the N-terminal tyrosine. Its molecular weight is approximately 5,135 daltons. The FDA approved tesamorelin in November 2010 under NDA 022505 and the brand name Egrifta for the reduction of excess abdominal fat in HIV-infected adults with lipodystrophy [19]. It is the only compound in either family with a current US marketing approval, limited to that single indication. The contrast between a GHRH analogue and a GHS-R1a pentapeptide is drawn out in the tesamorelin vs ipamorelin comparison. Research-grade tesamorelin supplied as a reference material is not the approved drug product.

Summary table

Compound	Receptor family	Residues	Origin	Key modification	Regulatory status
GHRP-6	GHS-R1a	6	Synthetic (Bowers program)	D-Trp2, D-Phe5, C-terminal amide	Never approved
GHRP-2 (pralmorelin)	GHS-R1a	6	Synthetic (Bowers scaffold, Kaken)	D-Ala1, D-2-Nal2, D-Phe5	Approved in Japan (2004) as a diagnostic; not FDA-approved
Hexarelin	GHS-R1a	6	Synthetic (GHRP-6 derivative)	D-2-Me-Trp2, D-Phe5	Never approved
Ipamorelin	GHS-R1a	5	Synthetic (Novo Nordisk, GHRP-1 scaffold)	Aib1, D-2-Nal3, D-Phe4; central Ala-Trp removed	Never approved
Sermorelin	GHRH receptor	29	Native GHRH(1-29) fragment	None (C-terminal amide only)	Formerly FDA-approved as Geref; discontinued, not for safety or effectiveness reasons
CJC-1295 without DAC	GHRH receptor	29	GHRH(1-29) fragment	D-Ala2, Gln8, Ala15, Leu27	Never approved
CJC-1295 with DAC	GHRH receptor	30	GHRH(1-29) fragment	Same four substitutions plus C-terminal Lys-maleimidopropionamide (albumin-binding)	Never approved; early-phase trials only
Tesamorelin	GHRH receptor	44	Native GHRH(1-44), full length	N-terminal trans-3-hexenoyl group	FDA-approved (2010) as Egrifta for one specific indication

Regulatory framing

Two further points of public record apply across both families. First, the World Anti-Doping Agency lists GHRH analogues and growth-hormone-releasing peptides under section S2 of its Prohibited List (peptide hormones, growth factors, related substances, and mimetics), and doping-control laboratories have published detection methods for members of both families: Okano and colleagues reported a liquid chromatography-tandem mass spectrometry method for pralmorelin and its metabolite in human urine in 2010 [20], and Henninge and colleagues reported the identification of CJC-1295 in an unlabeled pharmaceutical preparation the same year [21]. This listing reflects pharmacological class, not any record of approved use.

Second, regulatory status attaches to a compound, not to its class. Tesamorelin's approval does not extend to any other GHRH analogue, and pralmorelin's Japanese diagnostic approval does not extend to any other GHS-R1a agonist. Research-grade material of every compound named here is a laboratory reference material, not a pharmaceutical product, and is strictly for research use only.

Summary

The eight compounds are two families rather than one class. The GHS-R1a agonists (GHRP-6, GHRP-2, hexarelin, ipamorelin) are wholly synthetic peptides of five or six residues, built on the Bowers scaffold and characterized before their receptor or its natural ligand ghrelin was known. The GHRH analogues (sermorelin, CJC-1295 without DAC, CJC-1295 with DAC, tesamorelin) are 29- to 44-residue derivatives of the native hormone, differing by fragment length and by the chemistry added to resist enzymatic degradation. The two families act at different receptors, signal through different G proteins, and share no sequence. Only tesamorelin holds a current US approval, sermorelin formerly held one, pralmorelin holds a Japanese diagnostic approval, and the remaining five have never been approved anywhere.

References

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2. Rivier J, Spiess J, Thorner M, Vale W. Characterization of a growth hormone-releasing factor from a human pancreatic islet tumour. Nature. 1982;300(5892):276-278. PMID: 6292724
3. Mayo KE. Molecular cloning and expression of a pituitary-specific receptor for growth hormone-releasing hormone. Mol Endocrinol. 1992;6(10):1734-1744. PMID: 1333056
4. 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(5):1533-1540. PMID: 2565342
5. Momany FA, Bowers CY, Reynolds GA, Chang D, Hong A, Newlander K. Design, synthesis, and biological activity of peptides which release growth hormone in vitro. Endocrinology. 1981;108(1):31-39. PMID: 6109621
6. Bowers CY, Momany FA, Reynolds GA, Hong A. On the in vitro and in vivo activity of a new synthetic hexapeptide that acts on the pituitary to specifically release growth hormone. Endocrinology. 1984;114(5):1537-1545. PMID: 6714155
7. Howard AD, Feighner SD, Cully DF, et al. A receptor in pituitary and hypothalamus that functions in growth hormone release. Science. 1996;273(5277):974-977. PMID: 8688086
8. Kojima M, Hosoda H, Date Y, Nakazato M, Matsuo H, Kangawa K. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature. 1999;402(6762):656-660. PMID: 10604470
9. Bowers CY. Growth hormone-releasing peptide (GHRP). Cell Mol Life Sci. 1998;54(12):1316-1329. PMID: 9893708
10. Doi N, Hirotani C, Ukai K, et al. Pharmacological characteristics of KP-102 (GHRP-2), a potent growth hormone-releasing peptide. Arzneimittelforschung. 2004;54(12):857-867. PMID: 15646370
11. Pralmorelin: GHRP 2, GPA 748, growth hormone-releasing peptide 2, KP-102 D, KP-102 LN. Drugs R D. 2004;5(4):232-235. PMID: 15230633
12. Deghenghi R, Cananzi MM, Torsello A, Battisti C, Müller EE, Locatelli V. GH-releasing activity of hexarelin, a new growth hormone releasing peptide, in infant and adult rats. Life Sci. 1994;54(18):1321-1328. PMID: 7910650
13. Raun K, Hansen BS, Johansen NL, Thøgersen H, Madsen K, Ankersen M, et al. Ipamorelin, the first selective growth hormone secretagogue. Eur J Endocrinol. 1998;139(5):552-561. PMID: 9849822
14. Lance VA, Murphy WA, Sueiras-Diaz J, Coy DH. Super-active analogs of growth hormone-releasing factor (1-29)-amide. Biochem Biophys Res Commun. 1984;119(1):265-272. PMID: 6231028
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16. US Food and Drug Administration. Determination That GEREF (Sermorelin Acetate) Injection Was Not Withdrawn From Sale for Reasons of Safety or Effectiveness. Fed Regist. 2013 Mar 4;78(42):14002. Federal Register
17. Jetté L, Léger R, Thibaudeau K, et al. Human growth hormone-releasing factor (hGRF)1-29-albumin bioconjugates activate the GRF receptor on the anterior pituitary in rats: identification of CJC-1295 as a long-lasting GRF analog. Endocrinology. 2005;146(7):3052-3058. PMID: 15817669
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19. US Food and Drug Administration. Summary Review for Regulatory Action: Egrifta (tesamorelin for injection), NDA 022505. Silver Spring: FDA; 2010. FDA document
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21. Henninge J, Pepaj M, Hullstein I, Hemmersbach P. Identification of CJC-1295, a growth-hormone-releasing peptide, in an unknown pharmaceutical preparation. Drug Test Anal. 2010;2(11-12):647-650. PMID: 21204297