Sermorelin vs tesamorelin: the short GHRH fragment and the stabilised full-length analogue

The short version

Sermorelin and tesamorelin are both agonists at the receptor for growth-hormone-releasing hormone, and both are built from the human hormone itself. Sermorelin is the first 29 residues of GHRH, the shortest fragment with full activity, with nothing added. Tesamorelin is the whole 44-residue hormone with a small trans-3-hexenoyl group on its N-terminus. That one addition is the important difference: it protects the molecule from the enzyme that inactivates native GHRH within minutes. Sermorelin was once a licensed medicine in the United States and was withdrawn for commercial reasons; tesamorelin is licensed there today. Neither is licensed in the UK.

Both are supplied by BuyUK Peptides as research chemicals for in-vitro laboratory use only.

The enzyme problem both were designed around

Native GHRH is cut between alanine 2 and aspartate 3 by dipeptidyl peptidase-4 almost as soon as it enters plasma, leaving a fragment that no longer activates the receptor [1]. Every GHRH analogue in the research catalogue is an answer to that problem. Sermorelin does not solve it: it is simply the shortest active fragment, and it is cleaved just as quickly as the full hormone. CJC-1295 without DAC solves it by substituting D-alanine at position 2. Tesamorelin solves it differently, by capping the N-terminal amine with a hexenoyl group so that the enzyme cannot recognise its substrate, while leaving the full native sequence intact [2].

Structure and chemistry

The mass difference of about 1,778 Da makes the two unmistakable on an LC-MS identity line. Both contain a methionine at position 27, which is the main chemical weak point of the native sequence: it oxidises to the sulfoxide, adding 16 Da, on exposure to air and light.

Receptor pharmacology

Both act at the GHRH receptor, a class B G-protein-coupled receptor on pituitary somatotrophs that signals through Gs and cyclic AMP [3]. The extra fifteen residues of tesamorelin do not change which receptor it acts on; what changes is how long it survives in a biological medium. In a clean buffer system with no DPP-4 activity, both act as full agonists at the receptor, and potency comparisons depend heavily on the cell system used. In serum-containing media, or with cells that express the enzyme, sermorelin is inactivated within minutes and tesamorelin is not, which is often the more important variable in an in-vitro design.

The clinical and licensing record

Sermorelin was licensed in the United States as Geref, as a diagnostic agent in 1990 and for growth-hormone deficiency in children in 1997, on the basis of trials such as that reported by Thorner and colleagues [4] and reviewed by Prakash and Goa [5]. The manufacturer withdrew both products in 2008, and the FDA later determined that the withdrawal was not for reasons of safety or effectiveness [6].

Tesamorelin was licensed in the United States in 2010 as Egrifta, for excess abdominal fat in people with HIV-associated lipodystrophy, on the strength of two phase 3 trials [7]. Its later literature includes a randomised trial on liver fat in the same population [8]. A European application was withdrawn before a decision, and it has no marketing authorisation in the UK.

Regulatory and anti-doping status in the UK

Neither compound holds a UK marketing authorisation, and neither is a controlled drug. Both are supplied here as chemicals for in-vitro laboratory use under the Terms of Sale; our guide to the UK rules explains the position. Both are named on the WADA Prohibited List under S2.2 as GHRH analogues, prohibited at all times.

Handling at the bench

The two share the handling of the native hormone. Both are supplied lyophilised and keep for long periods sealed at −20 °C, or for months at 2 to 8 °C, protected from light. Both dissolve in water or bacteriostatic water, sometimes more cleanly in dilute acetic acid first. In solution, both are vulnerable to methionine oxidation and to deamidation of their asparagine residues, so reconstituted stocks should be kept cold, protected from light, used within a few weeks or aliquoted and frozen. Tesamorelin's N-terminal cap protects it from DPP-4, not from these chemical routes. Choosing a reconstitution solvent covers both.

What to look for on the certificate

RP-HPLC purity of 98 per cent or above for either. The LC-MS identity line should show about 3,357.9 Da for sermorelin and 5,135.9 Da for tesamorelin as deconvoluted masses. Look for the methionine sulfoxide at the main mass plus 16 Da, which elutes slightly earlier than the parent; a trace is normal, a few per cent is a sign of poor storage. For tesamorelin, a peak about 96 Da lighter than the parent would indicate loss of the hexenoyl group, which would leave a DPP-4-sensitive molecule.

Which to choose

For receptor pharmacology in a clean system, sermorelin is the reference ligand: it is the native active sequence with nothing added. For any design with serum, plasma or DPP-4-expressing cells, tesamorelin keeps its activity long enough to measure, and CJC-1295 without DAC is the other stabilised option. For the ghrelin-receptor side of the growth-hormone axis, see ipamorelin vs CJC-1295. Full accounts are in the monographs for sermorelin and tesamorelin.

References

1. Frohman LA, Downs TR, Heimer EP, Felix AM. Dipeptidylpeptidase IV and trypsin-like enzymatic degradation of human growth hormone-releasing hormone in plasma. Journal of Clinical Investigation. 1989;83(5):1533–1540. doi:10.1172/JCI114049.
2. Ferdinandi ES, Brazeau P, High K, Procter B, Fraser S, Dubreuil P. Non-clinical pharmacology and safety evaluation of TH9507, a human growth hormone-releasing factor analogue. Basic & Clinical Pharmacology & Toxicology. 2007;100(1):49–58. doi:10.1111/j.1742-7843.2007.00008.x.
3. Mayo KE. Molecular cloning and expression of a pituitary-specific receptor for growth hormone-releasing hormone. Molecular Endocrinology. 1992;6(10):1734–1744. doi:10.1210/mend.6.10.1333056.
4. Thorner M, Rochiccioli P, Colle M, et al. Once daily subcutaneous growth hormone-releasing hormone therapy accelerates growth in growth hormone-deficient children during the first year of therapy. Geref International Study Group. Journal of Clinical Endocrinology and Metabolism. 1996;81(3):1189–1196. doi:10.1210/jcem.81.3.8772599.
5. 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. doi:10.2165/00063030-199912020-00007.
6. 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. Federal Register. 2013;78(42):14095–14096. Docket FDA-2012-P-1071. govinfo.gov.
7. Falutz J, Allas S, Blot K, et al. Metabolic effects of a growth hormone-releasing factor in patients with HIV. New England Journal of Medicine. 2007;357(23):2359–2370. doi:10.1056/NEJMoa072375.
8. Stanley TL, Feldpausch MN, Oh J, et al. Effect of tesamorelin on visceral fat and liver fat in HIV-infected patients with abdominal fat accumulation: a randomized clinical trial. JAMA. 2014;312(4):380–389. doi:10.1001/jama.2014.8334.

This monograph summarises the published literature for laboratory researchers. It is not medical advice, and nothing on this site is for human or veterinary use.