Tesamorelin vs Sermorelin: Comparing GH Secretagogues
Tesamorelin and sermorelin are both analogues of growth hormone-releasing hormone, and both act on the same receptor. They differ in how each was engineered to survive in circulation — one by shortening the molecule, the other by capping it.
The molecule they are both derived from
Human growth hormone-releasing hormone is a 44-amino-acid peptide produced in the hypothalamus. It binds GHRH receptors on somatotroph cells in the anterior pituitary, prompting release of growth hormone.
Native GHRH has a short working life. It is cleaved by dipeptidyl peptidase-4 (DPP-4), an enzyme that removes the first two residues from the N-terminal end. That cleavage inactivates the molecule. The in vitro half-life of native human GHRH is approximately 0.56 hours.
The biological activity resides in the N-terminal region. The first 29 residues — GHRH(1-29) — constitute the shortest fragment that retains full activity.
Both compounds below start from these two facts and take different approaches to the degradation problem.
Sermorelin: the truncation approach
Sermorelin is GHRH(1-29), the minimum active fragment, with no further chemical modification.
The molecule is shortened to its functional core. Its chemistry at the N-terminus is unchanged from native GHRH, so it remains a DPP-4 substrate, and its circulating half-life is measured in minutes.
Development and approval. Sermorelin was approved in the United States as Geref, used in diagnostic assessment of growth hormone secretion and in the treatment of children with idiopathic growth hormone deficiency. The original manufacturer discontinued it, and it was withdrawn from the US market.
Tesamorelin: the capping approach
Tesamorelin retains the complete 44-residue human GHRH sequence and modifies it chemically at both ends.
Full designation: [trans-3-hexenoyl]hGHRH(1-44) amide. Development code TH9507.
N-terminal modification. A trans-3-hexenoyl group — a six-carbon side chain — is anchored to the N-terminal tyrosine residue. This cap occupies the site DPP-4 recognises, blocking the cleavage that inactivates native GHRH.
C-terminal amidation. The molecule terminates in an amide rather than a free carboxyl group, a modification that blocks carboxypeptidase attack.
Sequence: Trans-3-hexenoyl-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-Gln-Gln-Gly-Glu-Ser-Asn-Gln-Glu-Arg-Gly-Ala-Arg-Ala-Arg-Leu-NH₂
Molecular formula: C₂₂₁H₃₆₆N₇₂O₆₇S, supplied as the acetate salt.
Stability. The in vitro half-life of tesamorelin is 3 to 8 hours, against 0.56 hours for native human GHRH.
Development. Discovered by Theratechnologies scientists in 1995, with approximately fifteen years of development preceding FDA approval. Manufactured by FMOC solid phase peptide synthesis.
Clinical record
Tesamorelin
FDA approval, 2010 — marketed as Egrifta, indicated for reduction of excess abdominal fat in HIV-infected patients with lipodystrophy on antiretroviral therapy.
Visceral fat. Pivotal trials showed approximately 15 to 18 percent reduction in visceral adipose tissue over 26 weeks. The effect is selective for visceral rather than subcutaneous fat, and the product labelling describes tesamorelin as weight-neutral.
IGF-1 response. Daily 1 mg and 2 mg doses have been shown to raise IGF-1 into the physiological range observed in younger adults.
Liver. In a clinical trial in HIV patients with non-alcoholic fatty liver disease, tesamorelin reduced liver fat content and prevented progression of inflammation and fibrosis. Further trial work in NAFLD populations has followed.
Cognition. Investigated for effects on cognitive function in adults with cognitive impairment and in healthy older adults.
Antibody formation. A substantial proportion of treated patients develop anti-tesamorelin antibodies, with cross-reactivity to endogenous GHRH observed in a subset. Visceral fat reduction and IGF-1 response were comparable in patients with and without antibodies.
Contraindication. Not for use in patients with active malignancy. The labelling states that tesamorelin stimulates growth hormone production and raises IGF-1, and that the effects of prolonged IGF-1 elevation are unknown.
Sermorelin
Diagnostic use. Assessment of pituitary growth hormone secretory capacity.
Paediatric growth hormone deficiency. Treatment of children with idiopathic growth hormone deficiency.
Sermorelin’s approved product is no longer marketed. It remains available through compounding pharmacies.
Comparison
| Sermorelin | Tesamorelin | |
|---|---|---|
| Basis | GHRH(1-29) | GHRH(1-44) |
| Length | 29 residues | 44 residues |
| Stability strategy | Truncation to active fragment | N-terminal hexenoyl cap, C-terminal amide |
| DPP-4 susceptibility | Substrate | Cap blocks cleavage site |
| In vitro half-life | Comparable to native GHRH | 3–8 hours |
| Receptor | GHRH receptor | GHRH receptor |
| FDA approval | Previously approved, withdrawn | Approved 2010, current |
| Approved indications | Diagnostic; paediatric GHD | HIV-associated lipodystrophy |
| Principal trial outcome | Growth response in paediatric GHD | 15–18% visceral fat reduction at 26 weeks |
| Developer | Serono | Theratechnologies |
Shared characteristics
Both act on the GHRH receptor on pituitary somatotrophs and prompt release of endogenous growth hormone rather than supplying growth hormone directly.
Both operate within the axis’s feedback limits. Rising growth hormone raises IGF-1, and rising IGF-1 increases somatostatin tone, which suppresses further growth hormone release. Pituitary secretory capacity provides an additional ceiling.
Both require functioning pituitary tissue capable of producing growth hormone.
Both are administered by subcutaneous injection.
