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Sermorelin vs Ipamorelin: A Structural and Regulatory Comparison

A structural and regulatory comparison of sermorelin, the GHRH(1-29) fragment once marketed as Geref, and ipamorelin, an unapproved pentapeptide agonist of the ghrelin receptor GHS-R1a. Educational reference.

sermorelinipamorelinghrh-analogghs-r1agrowth-hormone-secretagoguegerefcomparison

Introduction

Sermorelin and ipamorelin are frequently compared because both are described as growth hormone secretagogues, but the label conceals a fundamental difference. Sermorelin is a fragment of a human hypothalamic hormone, growth-hormone-releasing hormone (GHRH), and was once an FDA-approved prescription product. Ipamorelin is a wholly synthetic five-residue peptide that acts at a different receptor, the growth hormone secretagogue receptor subtype 1a (GHS-R1a), and has never been approved in any jurisdiction. This article compares the two compounds on structure, origin, pharmacological class, regulatory status, and published research record. It reports what investigators and regulators have published and draws no conclusion about either compound's suitability for any purpose. Research-grade sermorelin and ipamorelin reference materials are cataloged with per-batch certificates of analysis.

Sermorelin: The GHRH(1-29) Fragment

Sermorelin's story begins with the native hormone. 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 GHRH sequence [1]. Structure-activity work followed rapidly. Lance, Murphy, Sueiras-Diaz, and Coy reported in 1984 on analogues of GRF(1-29)-amide, working from the finding that the first 29 residues of the hormone retained full receptor activity [2]. That N-terminal fragment, GHRH(1-29)-NH2, is sermorelin.

The receptor sermorelin engages was characterized a decade later. Mayo reported the molecular cloning and expression of a pituitary-specific receptor for growth-hormone-releasing hormone in Molecular Endocrinology in 1992 [3]. The GHRH receptor is a class B G protein-coupled receptor on anterior pituitary somatotrophs that signals through Gs and cyclic AMP. Frohman and colleagues had earlier reported, in the Journal of Clinical Investigation in 1989, that dipeptidyl peptidase IV and trypsin-like enzymes degraded GHRH in plasma, which accounts for the short circulating half-life shared by sermorelin and the native hormone [4].

Clinical characterization of GHRH(1-29) accumulated through the late 1980s and 1990s. Corpas and colleagues reported on growth hormone and insulin-like growth factor-I measurements following GHRH(1-29) administration in a small study of older men, published in the Journal of Clinical Endocrinology and Metabolism in 1992 [5]. Prakash and Goa reviewed sermorelin's use in the diagnosis and treatment of children with idiopathic growth hormone deficiency in BioDrugs in 1999 [6].

Findings from research models and clinical populations do not establish safety or efficacy in any other context. Sparta Labs makes no claims about the use of this compound.

Sermorelin's regulatory history is distinctive within the secretagogue literature. It was approved by the FDA as Geref, in a diagnostic formulation and in 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 (sermorelin acetate) was not withdrawn from sale for reasons of safety or effectiveness, a determination that permits abbreviated new drug applications to reference the product [7]. No sermorelin product is currently marketed under an FDA approval. Additional background is covered in the sermorelin research overview and the sermorelin history articles.

Ipamorelin: A Selective GHS-R1a Pentapeptide

Ipamorelin descends from a separate research lineage, the growth-hormone-releasing peptide (GHRP) family, which originated in the laboratory of Cyril Bowers in the late 1970s when enkephalin-derived peptides were found to release growth hormone through a mechanism distinct from GHRH. The receptor responsible was cloned by Howard and colleagues at Merck in 1996 and named the growth hormone secretagogue receptor, GHS-R1a [8]. In 1999 Kojima and colleagues identified the endogenous ligand of that receptor, the acylated stomach peptide ghrelin, in Nature [9]. The synthetic secretagogues therefore predate the discovery of the natural hormone whose receptor they engage, the reverse of sermorelin's history.

Ipamorelin (development code NNC 26-0161) was identified in a structure-activity program at Novo Nordisk A/S in Denmark. Raun and colleagues reported in the European Journal of Endocrinology in 1998 that the pentapeptide Aib-His-D-2-Nal-D-Phe-Lys-NH2 released growth hormone in primary rat pituitary cells and in conscious swine with potency comparable to GHRP-6, while not significantly affecting ACTH, cortisol, or prolactin at concentrations far above its ED50 for growth hormone release; the authors titled the report "Ipamorelin, the first selective growth hormone secretagogue" [10]. Ankersen and colleagues described a further series of potent secretagogues derived from the ipamorelin template in the Journal of Medicinal Chemistry [11], and Johansen and colleagues published a comparative pharmacokinetic evaluation of ipamorelin, GHRP-2, and GHRP-6 in rats the same year [12].

The compound's only published late-stage human study is a phase 2 randomized, placebo-controlled proof-of-concept trial reported by Beck and colleagues in 2014, which evaluated the ghrelin mimetic in patients recovering from bowel-resection surgery [13]. Ipamorelin was never submitted for marketing approval and holds no approval from the FDA or the European Medicines Agency. The ipamorelin research overview covers its chemistry and discovery context, and the ipamorelin mechanism of action article covers the receptor pharmacology.

Structural Comparison

  • Origin. Sermorelin is a truncation of a human hormone: the first 29 residues of GHRH(1-44), amidated at the C-terminus, with the sequence otherwise native [1, 2]. Ipamorelin has no natural counterpart; it was designed by iterative medicinal chemistry beginning from the GHRP-1 scaffold [10, 11].
  • Length and composition. Sermorelin contains 29 standard L-amino acids. Ipamorelin contains five residues, three of which are non-natural: an N-terminal alpha-aminoisobutyric acid (Aib), a D-2-naphthylalanine, and a D-phenylalanine, closed by a C-terminal lysine amide [10].
  • Molecular size. Sermorelin's molecular weight is approximately 3.4 kilodaltons; ipamorelin's is approximately 712 daltons.
  • Stability chemistry. Sermorelin carries no stabilizing modification and, like native GHRH, is subject to dipeptidyl peptidase IV cleavage at its N-terminus [4]. Later GHRH analogues such as tesamorelin and CJC-1295 were engineered specifically to resist that cleavage, a contrast covered in the tesamorelin vs sermorelin comparison. Ipamorelin's D-residues and Aib residue were reported as design elements for conformational rigidity and enzymatic stability [10, 11].
  • Receptor. Sermorelin acts at the GHRH receptor, a class B G protein-coupled receptor coupled to Gs and cyclic AMP [3]. Ipamorelin acts at GHS-R1a, a class A G protein-coupled receptor coupled primarily to Gq and phospholipase C [8]. Neither is reported to engage the other's receptor.
  • Regulatory status. Sermorelin: formerly FDA-approved as Geref, discontinued, and determined in 2013 not to have been withdrawn for safety or effectiveness reasons [7]. Ipamorelin: never approved in any jurisdiction; investigational compound with early-phase human data [13].

Pharmacological Class Context

Sermorelin anchors the GHRH-analogue class, which also includes tesamorelin (the full-length hormone with an N-terminal acyl cap, FDA-approved in 2010) and the CJC-1295 series (GHRH(1-29) with stabilizing substitutions). Members of this class act at the hypothalamic hormone's own receptor and were characterized in the literature as preserving the physiologic feedback regulation of growth hormone secretion [3, 6]. Ipamorelin anchors the selective end of the GHS-R1a agonist class, which also includes GHRP-6, GHRP-2, and hexarelin, whose members act at the ghrelin receptor [8, 9].

The two classes are pharmacologically independent: different receptors, different G-protein coupling, and different second messengers. Published research has used compounds from each class as tools for dissecting the regulation of the growth hormone axis, and reviews of the secretagogue field routinely treat GHRH analogues and GHS-R1a agonists as distinct categories. Sermorelin and ipamorelin have never been tested head-to-head in a published trial, and this article accordingly makes no comparative efficacy statement.

Research-grade sermorelin and ipamorelin sold by chemical suppliers are laboratory reference materials, not pharmaceutical products, and are strictly for research use only.

References

  1. Guillemin R, Brazeau P, Böhlen P, Esch F, Ling N, Wehrenberg WB. Growth hormone-releasing factor from a human pancreatic tumor that caused acromegaly. Science. 1982;218(4572):585-587. PMID: 6812220
  2. 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
  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. Corpas E, Harman SM, Piñeyro MA, Roberson R, Blackman MR. Growth hormone (GH)-releasing hormone-(1-29) twice daily reverses the decreased GH and insulin-like growth factor-I levels in old men. J Clin Endocrinol Metab. 1992;75(2):530-535. PMID: 1379256
  6. 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. PMID: 18031173
  7. US Food and Drug Administration. Determination That GEREF (Sermorelin Acetate) Injection, 0.5 Milligrams Base/Vial and 1.0 Milligrams Base/Vial, and GEREF (Sermorelin Acetate) Injection, 0.05 Milligrams Base/Amp, Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness. Fed Regist. 2013 Mar 4;78(42):14002. Federal Register
  8. 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
  9. 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
  10. 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
  11. Ankersen M, Johansen NL, Madsen K, Hansen BS, Raun K, Nielsen KK, et al. A new series of highly potent growth hormone-releasing peptides derived from ipamorelin. J Med Chem. 1998;41(19):3699-3704. PMID: 9733495
  12. Johansen PB, Hansen KT, Andersen JV, Johansen NL. Pharmacokinetic evaluation of ipamorelin and other peptidyl growth hormone secretagogues with emphasis on nasal absorption. Xenobiotica. 1998;28(11):1083-1092. PMID: 9879640
  13. Beck DE, Sweeney WB, McCarter MD, et al. Prospective, randomized, controlled, proof-of-concept study of the Ghrelin mimetic ipamorelin for the management of postoperative ileus in bowel resection patients. Int J Colorectal Dis. 2014;29(12):1527-1534. PMID: 25331030

Frequently asked questions

  • What is the difference between sermorelin and ipamorelin?

    Sermorelin is the 29-amino-acid N-terminal fragment of human growth-hormone-releasing hormone (GHRH) and acts at the GHRH receptor. Ipamorelin is a five-residue synthetic peptide that acts at the growth hormone secretagogue receptor GHS-R1a, later identified as the ghrelin receptor. They belong to different pharmacological classes, engage different receptors, and have separate discovery and regulatory histories.

  • Is sermorelin FDA approved?

    Sermorelin was approved by the FDA under the brand name Geref, with a diagnostic formulation and a formulation indicated for pediatric growth hormone deficiency. The products were later discontinued, and in a 2013 Federal Register notice the FDA determined that Geref was not withdrawn from sale for reasons of safety or effectiveness. No sermorelin product is currently marketed under an FDA approval in the United States.

  • Is ipamorelin FDA approved?

    No. Ipamorelin has never received marketing approval from the FDA or the European Medicines Agency. Its published human data are limited to early-phase clinical trials, and it is supplied only as a research-use-only material.

  • What is sermorelin?

    Sermorelin is GHRH(1-29)-NH2, the shortest N-terminal fragment of native GHRH reported to retain full activity at the GHRH receptor. It was characterized in the early 1980s following the isolation of native GHRH by Guillemin and colleagues, and it was later developed into the diagnostic and pediatric product Geref.

  • What is ipamorelin?

    Ipamorelin (development code NNC 26-0161) is a synthetic pentapeptide with the sequence Aib-His-D-2-Nal-D-Phe-Lys-NH2, developed at Novo Nordisk in the 1990s. Raun and colleagues described it in 1998 as the first selective growth hormone secretagogue based on its reported hormonal profile in preclinical models.

  • Do sermorelin and ipamorelin act on the same receptor?

    No. Sermorelin acts at the GHRH receptor, a class B G protein-coupled receptor cloned by Mayo in 1992 that signals through Gs and cyclic AMP. Ipamorelin acts at GHS-R1a, a class A G protein-coupled receptor cloned by Howard and colleagues in 1996 that signals primarily through Gq and phospholipase C.

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