Growth hormone secretagogues: what they are and why four peptides keep showing up together

Four peptides keep showing up together on the longevity menu — CJC-1295, ipamorelin, sermorelin, and tesamorelin. They get marketed in stacks, talked about as variations on one drug, and routinely confused for each other in product copy.

Here is what they actually are, and why one of them is a real prescription medicine and the other three are something else.

What a growth hormone secretagogue actually does

The category the four sit inside is growth hormone secretagogue. The word sounds technical and the idea is plain. A secretagogue is anything that signals a gland to release something it already makes. In this case the gland is the pituitary, the something is growth hormone, and the four peptides all push the pituitary to release more of it. They do not deliver growth hormone — they ask the body’s own release machinery to work harder.

There are two doors into that machinery, and the four peptides split between them.

The first door is the GHRH receptor. Growth-hormone-releasing hormone is the natural signal from the hypothalamus that tells the pituitary to fire. CJC-1295, sermorelin, and tesamorelin all act through this receptor. They are synthetic analogs of GHRH — imitating the upstream signal.

The second door is the ghrelin receptor (also called GHSR-1a). Ghrelin is the hunger hormone, but the same receptor it works through also triggers growth hormone release. Ipamorelin acts through this door — a ghrelin-mimic, not a GHRH-mimic. Different upstream signals, same downstream output: the pituitary releases growth hormone, which drives a rise in IGF-1 in the liver. That is the class resemblance.

CJC-1295 and the DAC question

CJC-1295 is a 30-amino-acid GHRH analog identified in a 2005 Endocrinology paper by the originating group at ConjuChem. They synthesised three albumin-binding derivatives of GHRH(1-29) and bioconjugated each to human serum albumin. The point was a longer half-life — unmodified GHRH is cleared in minutes.

It worked. The CJC-1295 with DAC variant (DAC = drug affinity complex, the albumin-binding handle) has a plasma half-life of roughly 6–8 days. The same compound without DAC — sometimes labelled MOD-GRF(1-29) — has a half-life closer to 30 minutes. Two distinct chemistries, both sold as “CJC-1295” on the research-chemical market, and they are not interchangeable.

The Teichman 2006 Phase 1 trial in JCEM is the only well-characterised human study of the DAC form. It raised mean plasma GH 2- to 10-fold above baseline for up to six days, with IGF-1 up 1.5- to 3-fold for nine to eleven days, and reported no serious adverse events at the doses tested. It is also the only registered controlled human trial of CJC-1295 at any size. Twenty years on, the compound has not advanced to Phase 2 or Phase 3 for any indication.

Ipamorelin and the trial that read null

Ipamorelin is a five-amino-acid pentapeptide, a synthetic ghrelin-receptor agonist designed at Novo Nordisk in the 1990s as the selective GH secretagogue — meaning it triggers growth hormone release without the cortisol and prolactin spikes the older GHRPs caused. The selectivity profile is real and is the legitimate mechanistic differentiator versus its older relatives.

The clinical evidence is the smaller half of the story. The pivotal trial — Beck et al. 2014, a Phase 2 randomised double-blind multicenter study in 117 bowel-resection patients — tested ipamorelin for postoperative ileus. Median time to first tolerated meal was 25.3 hours on ipamorelin vs 32.6 hours on placebo. The number looks suggestive. The p-value, 0.15, says it did not reach statistical significance. The primary efficacy endpoint was null, and Helsinn discontinued the postoperative-ileus development program. That trial is the only registered controlled human trial of ipamorelin at clinical scale.

Sermorelin and tesamorelin — the two with FDA approval files

Sermorelin is GHRH(1-29) — the first twenty-nine amino acids of native GHRH. The fragment retains receptor-binding activity but is missing the rest of the molecule. Sermorelin once held FDA approval in the United States as Geref (Serono) for diagnostic use and paediatric growth hormone deficiency. FDA formally withdrew the Geref NDAs (019863 diagnostic, 020443 paediatric) on June 18, 2009, for commercial reasons — not safety or efficacy. The active ingredient stayed available through Section 503A pharmacy compounding, which is where the off-label adult longevity market lives today.

The published human evidence in healthy adults is thinner than the marketing implies. The 1997 Vittone paper in Metabolism tested single nightly subcutaneous GHRH(1-29) injections in healthy elderly men and showed measurable GH/IGF-1 movement. Two early Khorram papers from the same year used a stabilised analog — [Nle27]GHRH(1-29) — with a norleucine substitution at position 27. That is not strictly sermorelin, and the structural-nomenclature point matters: the older healthy-adult studies often used the stabilised analog, not the molecule actually sold.

Tesamorelin is the only one of the four with a current FDA drug approval on file. The 2007 Falutz Phase III in NEJM randomised 412 HIV-infected adults with abdominal-fat accumulation to once-daily tesamorelin or placebo for 26 weeks. Visceral adipose tissue fell 15.2 percent on tesamorelin and rose 5.0 percent on placebo. That trial earned the Egrifta approval (NDA 022505, November 2010) for one indication in one population. Everything else — the cognition use, the longevity case, the non-HIV abdominal-obesity question — is off-label.

The most consequential paper in the longevity discourse about this class is Baker et al. 2012, Arch Neurol. 152 adults with mild cognitive impairment and healthy older controls, 20 weeks of nightly subcutaneous treatment, favourable cognition effect at p=0.03. The intervention was tesamorelin, not sermorelin. The trial gets miscited as sermorelin evidence in marketing copy almost every time it appears.

What “GH secretagogue” does not tell you

The class label collapses four distinct files. CJC-1295 has a Phase 1 PK/PD trial from 2006 and twenty years of nothing else. Ipamorelin has a Phase 2 trial that read null. Sermorelin has an old FDA approval that was withdrawn for commercial reasons and a thin healthy-adult evidence base often built on a different analog. Tesamorelin has a live FDA approval for HIV lipodystrophy and a single positive cognition trial in non-HIV older adults.

The regulatory standing splits the same way. PCAC reviewed CJC-1295 and ipamorelin in late 2024 — December 4 and October 29 respectively, after both were removed from the Section 503A Category 2 ban list earlier that year — and the committee voted against including either on the 503A bulk substances list. Sermorelin is not on the 2026–2027 PCAC dockets and operates today through Section 503A compounding under state pharmacy authority. Tesamorelin is not on the dockets either, per the April 2026 Federal Register notice, because it sits under the approved-drug pathway (Egrifta WR, NDA 022505) — and Section 503A specifically restricts copying active moieties of approved drugs. Four molecules. Same receptor family. Four different regulatory files. We covered how PCAC reviews actually work in What is the PCAC.

The Mavrych 2026 review in Frontiers in Aging covers all four molecules in the growth-hormone-modulation cluster and flags exactly the gap this article is named after: significant unknowns around optimal dosing, combination effects, and validated efficacy biomarkers across the class.

Same family, four files

What this class is not is a single drug with four labels. The receptor target is the family resemblance. The evidence base is what each peptide does and does not have on its own. For the buyer, that means the prescribing question is rarely a clean read on biology — it is a read on which file a physician is willing to defend in writing. And those files look different per peptide.

CJC-1295’s file is a single Phase 1 from 2006, twenty years of nothing else, and a 2024 PCAC vote against compounding inclusion. Ipamorelin’s file is a clean selectivity story, a null Phase 2 in a non-injury indication, and the same 2024 PCAC vote against. For both of those compounds the legitimate-prescription question in the US is open in name and closed in practice for now.

Sermorelin’s file is a withdrawn FDA approval (commercial, not safety), a 1997 healthy-adult dataset that often turns out to be a different analog, and an open Section 503A compounding pathway because the active ingredient has no current FDA application. The prescribing question for it is the most open of the four. Tesamorelin’s file is a current FDA approval for HIV lipodystrophy, a small non-HIV randomised trial, the most-misattributed cognition study in the cluster, and a compounding pathway constrained by the approved-drug overlap. The on-label question is well-defined; the off-label is everything else.

Four files, four different conversations with a supervising physician. Wolverine Health is being built so those conversations actually happen — physician-supervised peptide protocols, US-licensed compounding pharmacies, every batch third-party tested. Join the waitlist for a note the day any of those four files moves.