The growth-hormone axis, and four ways to poke it

Pulsatility is the point

Growth hormone is not secreted at a steady rate. The pituitary releases it in bursts, largest in early sleep, under the opposing influence of hypothalamic GHRH, which promotes release, and somatostatin, which suppresses it. Downstream, most of the peripheral signalling runs through hepatic IGF-1.

The pulsatile pattern is biologically meaningful rather than incidental — receptor desensitisation, target-tissue response and feedback all track the pattern, not just the total. This is why any account of these compounds that reduces to a single quantity of hormone released is missing the variable that matters most, and why a compound preserving pulsatility and one flattening it are doing different things.

The GHRH side

Native GHRH was characterised in 1982 by Guillemin and colleagues in Science, isolated from a pancreatic tumour that had produced acromegaly in its host — a natural experiment that identified the factor and its 44-residue sequence at once. Rivier and colleagues reported the primary structures in Nature the same year.

Sermorelin is GHRH(1-29), the shortest N-terminal fragment retaining receptor activity, with a plasma half-life of minutes. Tesamorelin is a trans-3-hexenoyl-modified GHRH(1-44) analogue, the modification conferring protease resistance. CJC-1295 is a GHRH(1-29) analogue with substitutions that resist cleavage; the variant carrying a drug-affinity complex that binds serum albumin has a far longer circulating life than the variant without it, which is precisely why both exist as separate catalog entries.

Because these act at the pituitary GHRH receptor, release remains subject to somatostatin feedback. That is the mechanistic argument for this class: the ceiling is retained.

What the tesamorelin programme established

Falutz and colleagues reported a randomised placebo-controlled trial of tesamorelin in the New England Journal of Medicine in 2007, in patients with HIV-associated central fat accumulation. The primary outcome was visceral adipose tissue measured by CT. The trial reported a reduction in visceral adipose tissue in the treatment arm relative to placebo, with associated changes in the lipid profile, and the compound was subsequently approved for that specific indication.

This is the strongest human evidence anywhere in this group of compounds, and its scope should be read precisely: a defined population with a defined pathology, a radiographically measured body-composition endpoint, and an approval limited to that indication. It is not a general finding about growth-hormone secretagogues, about body composition in healthy adults, or about anything else.

The ghrelin-receptor side, and the selectivity question

Ghrelin's receptor, GHS-R1a, was identified as a growth-hormone secretagogue receptor before its endogenous ligand was known. Compounds acting there release growth hormone by a route independent of the GHRH receptor, and in the early generation they released a good deal else besides — adrenocorticotropin, cortisol and prolactin among them.

Raun and colleagues, in the European Journal of Endocrinology in 1998, characterised ipamorelin against that background and reported growth-hormone release in the models tested without the accompanying cortisol and prolactin elevation seen with earlier secretagogues, which is the basis for describing it as the first selective compound of its class. Hexarelin, from the same broad family, is reported in the literature with a less selective profile and has been examined additionally for cardiac effects.

Selectivity is therefore a property of the individual molecule, not of the class, and the distinction is doing real work in how these compounds behave in an experiment.

How the catalog reflects this

The Endocrine world groups these compounds together but the pages distinguish them by receptor and by half-life, because those are the axes on which they actually differ. Research targets named there are growth-hormone axis signalling, IGF-1 response, and receptor selectivity in the assay systems used.

Nothing on those pages describes an effect in a person, and no dosing appears anywhere. Tesamorelin's approval is for a named indication in a named population and is not a general endorsement of the class; the others are not approved drugs in the United States. All of these compounds fall under WADA's prohibited peptide-hormone and secretagogue categories.