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ComparisonSermorelin

GHRH analogues and ghrelin receptor agonists: two receptors

Sermorelin, tesamorelin and CJC-1295 act at the GHRH receptor; ipamorelin acts at GHSR-1a. Two receptors, two structural families, why the Prohibited List enumerates them separately, and how the evidence differs.

Last reviewed
2026-09-22
Reviewer
editorial review pending
Revision
1
Sources
50

Summary

Four compounds in this knowledge base raise circulating growth hormone, and they do so through two different receptors. Sermorelin, tesamorelin and CJC-1295 are assigned to the growth hormone-releasing hormone receptor, also written as the GRF receptor 1234. Ipamorelin is assigned to growth hormone secretagogue receptor type 1a, GHSR-1a, the ghrelin receptor 567. The receptor split coincides with a structural split: the first three are the human GHRH sequence or a modified fragment of it, whereas ipamorelin is not a fragment or analogue of any human protein sequence 89247.

Two receptors

The GHRH receptor was cloned as a seven-transmembrane G protein-coupled receptor of the secretin and vasoactive intestinal peptide receptor family, expressed predominantly in the anterior pituitary, and GHRH binding stimulates intracellular cyclic AMP production in transfected cells 10. ChEMBL records the mechanism of sermorelin as growth hormone-releasing hormone receptor agonist against target CHEMBL2032 1. The US label for tesamorelin states that the compound binds and stimulates human GRF receptors in vitro with potency similar to endogenous GRF, and that GRF acts on pituitary somatotrophs to stimulate the synthesis and pulsatile release of endogenous growth hormone 2. Both forms of CJC-1295 are assigned to the same receptor, although for the DAC form that assignment rests on direct pharmacology and for the non-DAC form on class alone, FDA having stated that no study identified establishes whether the non-DAC substance is pharmacologically active 34.

The second receptor is unrelated in family and in ligand. Ipamorelin was characterised as acting through a growth hormone-releasing peptide receptor, demonstrated by profiling growth hormone release against growth hormone-releasing peptide and GHRH antagonists; the receptor was identified as GHSR-1a in later regulatory and database records, and the FDA substance registry records a target-agonist relationship to it directly 756. The original characterisation reported release of growth hormone from primary rat pituitary cells with an EC50 of 1.3 plus or minus 0.4 nmol/L, and described selectivity as the distinguishing finding: unlike growth hormone-releasing peptide-6 and growth hormone-releasing peptide-2, ipamorelin did not raise plasma ACTH or cortisol above GHRH-stimulated levels even at exposures more than 200-fold above the ED50 for growth hormone release, and no effect on FSH, LH, prolactin or TSH was observed in swine 7.

Two structural families

The three GHRH analogues share one scaffold and differ in how they modify it. Sermorelin is the C-terminally amidated 1-29 fragment of human growth hormone-releasing hormone, its sequence identical to residues 1-29 of mature somatoliberin, with amidation as its only modification 8911. Tesamorelin is the 44-residue human GRF(1-44) amide carrying a trans-3-hexenoyl group, a six-carbon chain with a double bond at position 3, on the N-terminal tyrosine; the substance registry encodes exactly two structural modifications, at positions 1 and 44 21213. CJC-1295 is the same 1-29 fragment carrying four substitutions, D-alanine at position 2, glutamine at position 8, alanine at position 15 and leucine at position 27, with the DAC form extended by a thirtieth lysine whose side chain bears a 3-maleimidopropionamide group 4314.

Those modifications map onto known liabilities of the shared scaffold. Dipeptidyl peptidase IV cleaves GRF peptides including GRF(1-29)-NH2 at the 2-3 bond, and Asp3 isomerisation, Asn8 deamidation and Met27 oxidation are the three chemical liabilities of the sequence 15161718. Tesamorelin addresses the first by N-terminal acylation: no degradation was observed on incubation with dipeptidyl peptidase-IV, and the in vitro half-life in human plasma was reported as roughly six- to fifteen-fold that of unmodified hGRF depending on conditions 1912. Unmodified sermorelin was entirely degraded after four hours of incubation in human plasma at 37 °C, with DPP-IV as the principal enzyme 2015.

Ipamorelin shares none of this. It is the pentapeptide Aib-His-D-2-Nal-D-Phe-Lys-NH2, in which three of the five positions are occupied by residues that are either not proteinogenic or not in the L configuration: 2-aminoisobutyric acid at the N-terminus, D-3-(2-naphthyl)alanine at position 3 and D-phenylalanine at position 4 75621. No standard one-letter sequence exists for it, because that code is defined only for the twenty proteinogenic L-residues, and FDA records that such residues add to the complexity of characterisation 216.

Why the Prohibited List enumerates them separately

Section S2.2.4 of the Prohibited List in force is headed growth hormone releasing factors, and within that single heading it enumerates the two families separately. Growth hormone-releasing hormone and its analogues are given with CJC-1293, CJC-1295, sermorelin and tesamorelin as examples, while growth hormone secretagogues and their mimetics are given with ipamorelin alongside anamorelin, capromorelin, ibutamoren, lenomorelin, macimorelin and tabimorelin 2223. Class S2 is prohibited at all times 22.

The structure of that section follows the pharmacology rather than the outcome. A shared downstream effect on growth hormone release is not what defines the entries; each sub-enumeration names a ligand family for one receptor, and the class wording extends to substances with a similar chemical structure or similar biological effect, which is how new members of either family are reached 22. The list does not distinguish the DAC and non-DAC forms of CJC-1295; both fall within the named example 22.

How the evidence bases differ

Within the GHRH family the evidence is uneven, and the family contains both the only compound of the four with a current authorisation and the only one whose authorisation has ended. Tesamorelin acetate has been licensed in the United States since 10 November 2010 under application 022505, on the strength of two 26-week randomised phase 3 trials with 412 and 404 participants, re-randomised 26-week extensions and a pooled analysis of 806 participants, with later investigator-initiated randomised trials in liver fat, type 2 diabetes and neurocognitive endpoints 2425262728; the EU centralised application was withdrawn on 21 June 2012 29. Sermorelin acetate was approved in the United States under two applications, in 1990 and 1997, both withdrawn at the holder's request effective 18 June 2009, and FDA determined in 2013 that the withdrawal was not for reasons of safety or effectiveness 303132. Its human literature is small and mostly predates trial registration: one multicentre open-label paediatric efficacy study in 110 children, early clinical pharmacology work, and one open uncontrolled study in 11 older men 333435. CJC-1295 has never been authorised; the DAC form was studied in three phase 1 trials in healthy adults with 42, 24 and 12 participants and entered a phase 2 trial terminated in 2006 and never published, while no human or animal study of the non-DAC form was identified 3637384.

The GHSR-1a side has no authorisation anywhere. No marketing authorisation for ipamorelin was found in the United Kingdom, the European Union or the United States, and the human programme consists of one phase 1 intravenous study in 48 healthy men and two phase 2 trials in postoperative ileus, of which the published trial in 117 participants did not separate from placebo on its primary endpoint and the larger trial in 320 participants carries no posted results and no located publication 39404142434445. In October 2024 the FDA Pharmacy Compounding Advisory Committee voted against placing either the free base or the acetate on the 503A bulk drug substances list, and in December 2024 it rejected all five CJC-1295-related substances 4647.

Evidence level

GHRH receptor family: one licensed compound with published phase 3 evidence, one with a licensed history that ended and a pre-registry literature, and one investigational compound whose phase 2 trial was terminated unpublished 253338. GHSR-1a family: nonclinical characterisation, one phase 1 study and two phase 2 trials, neither of which produced a positive published primary result 74445.

Open questions

Neither family is fully characterised. No pharmacopoeial monograph exists for ipamorelin in the United States, European, Chinese, Indian or Japanese pharmacopoeias, none was retrieved for CJC-1295 or tesamorelin, and the position for sermorelin was not checked because the relevant compendia are not openly fetchable 641911. The outcome of the larger ipamorelin phase 2 trial is unverified, no primary publication having been located 45. Whether the non-DAC form of CJC-1295 has any pharmacological activity at the GHRH receptor is unestablished by any study identified by FDA 4. And the analytical literature for both families comes overwhelmingly from doping control rather than from pharmacopoeial work: the GHRH analogues are identified in plasma by immunoaffinity purification with liquid chromatography and high-resolution tandem mass spectrometry, and the secretagogues in urine by solid-phase extraction with liquid chromatography and mass spectrometry 20484950.

Questions this page answers

What separates a GHRH analogue from a growth hormone secretagogue?
The receptor. Sermorelin, tesamorelin and CJC-1295 are assigned to the growth hormone-releasing hormone receptor, a seven-transmembrane G protein-coupled receptor of the secretin and VIP family expressed predominantly in the anterior pituitary. Ipamorelin is assigned to growth hormone secretagogue receptor type 1a, the ghrelin receptor. The two families are also structurally unrelated.
Are the GHRH analogues fragments of a human sequence?
All three derive from human growth hormone-releasing hormone. Sermorelin is the C-terminally amidated 1-29 fragment with no other modification. Tesamorelin is the 44-residue sequence with a trans-3-hexenoyl group on the N-terminal tyrosine. CJC-1295 is the 1-29 fragment with four substitutions, and in its DAC form a thirtieth lysine carrying a maleimidopropionamide group.
Why does the WADA Prohibited List list both families under S2.2.4?
Section S2.2.4, growth hormone releasing factors, enumerates the two families separately within one heading: growth hormone-releasing hormone and its analogues, with CJC-1293, CJC-1295, sermorelin and tesamorelin as examples, and growth hormone secretagogues and their mimetics, with ipamorelin alongside anamorelin, capromorelin, ibutamoren, lenomorelin, macimorelin and tabimorelin. Class S2 is prohibited at all times.
Which of these compounds has been an authorised medicine?
Two. Tesamorelin acetate has been the active ingredient of a US-licensed product since 10 November 2010 under application 022505. Sermorelin acetate was approved in the United States as Geref under two applications, both withdrawn at the holder's request effective 18 June 2009; FDA determined in 2013 that the withdrawal was not for reasons of safety or effectiveness. Neither CJC-1295 nor ipamorelin has been authorised anywhere.
Is the published human evidence comparable between the two families?
No. Tesamorelin rests on two randomised phase 3 trials with extensions and a pooled analysis of 806 participants. Sermorelin's literature is small and mostly predates trial registration. CJC-1295 has three phase 1 studies of the DAC form and a terminated, unpublished phase 2 trial, with no study of the non-DAC form identified. Ipamorelin has one phase 1 study and two phase 2 trials, one of which missed its primary endpoint and one of which posted no results.

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For laboratory research use only. This article summarises published literature and regulatory records; it does not describe or recommend any use of a material in or on humans or animals.
Cite this page
Harvard
HelixEVO Labs (2026) GHRH analogues and ghrelin receptor agonists: two receptors. Available at: https://helixevo.net/knowledge-base/comparisons/ghrh-analogues-vs-ghrelin-receptor-agonists (Accessed: 2026-09-25).
APA
HelixEVO Labs. (2026). GHRH analogues and ghrelin receptor agonists: two receptors. https://helixevo.net/knowledge-base/comparisons/ghrh-analogues-vs-ghrelin-receptor-agonists
BibTeX
@misc{helixevo-2026-ghrh-analogues-and-ghrelin-receptor-agon,
  title = {GHRH analogues and ghrelin receptor agonists: two receptors},
  author = {{HelixEVO Labs}},
  year = {2026},
  howpublished = {\url{https://helixevo.net/knowledge-base/comparisons/ghrh-analogues-vs-ghrelin-receptor-agonists}},
  note = {Reviewed 2026-09-22; accessed 2026-09-25}
}
Revision history
  1. r1 · 2026-09-25 · Initial import