Cyril Bowers and the hormone nobody was looking for — the discovery of GHRPs
In 1976, an endocrinologist in New Orleans stumbled on a tiny peptide trace that released growth hormone — through a receptor nobody knew about. It became a family of substances (GHRP-2, GHRP-6, ipamorelin) and in 1999 led to the discovery of the ghrelin receptor. A story about a researcher who followed an anomaly for 20 years.
An observation at the margin of a standard assay
In the mid-1970s, Cyril Bowers worked at Tulane University in New Orleans on a classical endocrinology topic: the growth hormone control loop. Growth-hormone-releasing hormone (GHRH) had not yet been isolated, but known substances such as met-enkephalin were routinely tested for pituitary stimulation. Bowers stumbled on an unexpected observation: a met-enkephalin analog with five modified amino acids stimulated growth hormone release in vitro much more strongly than the parent peptide — and in a pattern that could not be explained by the opioid receptors known at the time.
That was 1976. Bowers published the finding as a short communication in 1977. Nobody was particularly interested: GHRH was isolated in 1982 by Roger Guillemin and Wylie Vale from pancreatic tumours, and the entire growth-hormone research mainstream focused on the GHRH receptor. Bowers' anomalous met-enkephalin analog was a footnote — but he did not let it go.
Two decades of structural optimisation
Over the 1980s and 1990s, Bowers — first with Frank Momany and later with various industry partners — systematically expanded the observation. From the original met-enkephalin trace emerged a family of synthetic peptides that all did the same thing: release growth hormone, independent of GHRH but synergistic with GHRH when both were present.
- GHRP-6 (His-D-Trp-Ala-Trp-D-Phe-Lys-NH₂, 1984) — the first clinically used representative, orally active at higher doses.
- GHRP-2 (pralmorelin, 1990s) — more compact sequence, higher potency; later approved in Japan as a diagnostic tool.
- Hexarelin (1990s) — methylated variant, phase-2 trials for GH deficiency.
- Ipamorelin (1998, Novo Nordisk) — selective for GH release, no rise in cortisol or prolactin.
In parallel, Merck developed an orally available non-peptide ligand of the same class: MK-0677 (ibutamoren). All these substances apparently bound to the same unknown receptor — referred to in the literature as the 'Growth Hormone Secretagogue Receptor' (GHS-R), because its endogenous ligand was still unknown.
The receptor in search of its ligand
In 1996 the GHS-R was identified by cloning (Howard et al., Science). That made it clear: a specific receptor exists that does not function via GHRH. But which endogenous substance activates it? Bowers' synthetic GHRPs could not possibly be the natural ligands — they were synthetically designed. The search for the endogenous ligand ran for three years.
In 1999, Masayasu Kojima in Tokyo published the answer in Nature: ghrelin. A 28-amino-acid peptide with an unusual n-octanoyl modification at serine-3, isolated from gastric tissue. Ghrelin bound the GHS-R, stimulated growth hormone release — and later turned out to be a central hunger signal. The story was complete: Bowers had been designing synthetic ligands since 1976 for a receptor whose natural partner was found only 23 years later.
„We didn't know for a long time what we were doing. We only knew that it released growth hormone and that it was not GHRH. The rest took 20 years."
What became of the GHRPs clinically — and what did not
Despite the elegantly elucidated biology, the clinical career of the GHRPs is mixed. Ipamorelin did not advance beyond phase 2/3 to approval. GHRP-2 is used in Japan as a diagnostic test. Hexarelin was investigated in phase 2 trials for GH deficiency and heart failure, but never approved. Ibutamoren (MK-0677) reached phase 3 for sarcopenia and GH deficiency, but failed on elevated HbA1c and oedema — pointing to insulin-relevant side effects via the ghrelin axis.
In the anti-aging and bodybuilding scene, the same substances led a parallel shadow life from the 2000s on as research chemicals. WADA banned GHRPs from 2012 as part of the growth hormone axis. Bowers himself continued to publish academic work on the GHRP family into the 2010s.
Open questions
- Why did none of the GHRPs make the clinical market — safety concerns, lack of differentiation from recombinant GH, or regulatory hurdles?
- What role does the ghrelin axis play beyond growth hormone — appetite, cardiovascular effects, memory?
- Can new, ghrelin-receptor-specific ligands with better-separated effect profiles be developed (e.g. only GH release without insulin effects)?