Sermorelin — GHRH(1-29), diagnostic and anti-aging GHRH analog
Synthetic 29-aa N-terminal GHRH fragment; FDA-approved for GH deficiency diagnosis in children; off-label anti-aging and GH optimization; stimulates pulsatile endogenous GH; short t½ requires daily dosing
- Class
- GHRH analog (synthetic GHRH 1-29)
- Status
- Not currently FDA-approved as a commercial product; available in the US through state-licensed compounding pharmacies for off-label use. WADA prohibited at all times (class S2).
- Best-supported effect
- Stimulation of pulsatile endogenous growth hormone release; clinical efficacy demonstrated in pediatric idiopathic growth hormone deficiency (FDA approval-era trials).
- Main caveat
- The pediatric GHD evidence base predates the modern recombinant-GH treatment landscape, and the compounding-era adult off-label uses (anti-aging, sleep, body composition) have not been validated in dedicated controlled adult trials.
A researcher, an agent, or an algorithm wrote down the sequence and picked a target to hit.
An AI model like OpenFold3 or AlphaFold built a 3D structure and scored how well it fits the binding site.
A second contributor repeated the computation on their own hardware and the scores matched.
A chemistry service or a researcher ordered the sequence, it was manufactured, and mass spectrometry confirmed the right molecule was produced.
A binding or activity measurement confirmed that it actually does what the computer predicted — or didn't.
Snapshot
Class: GHRH analog (synthetic GHRH 1-29)
Evidence tier: Human clinical evidence
Status: Not currently FDA-approved as a commercial product; available in the US through state-licensed compounding pharmacies for off-label use. WADA prohibited at all times (class S2).
Best-supported effect: Stimulation of pulsatile endogenous growth hormone release; clinical efficacy demonstrated in pediatric idiopathic growth hormone deficiency (FDA approval-era trials), the indication that supported the 1997 Geref approval.
Main caveat: The pediatric GHD evidence base predates the modern recombinant-GH treatment landscape, and the compounding-era adult off-label uses (anti-aging, sleep, body composition) have not been validated in dedicated controlled adult trials.
What this is
Sermorelin is a synthetic 29-amino-acid peptide corresponding to the N-terminal fragment of human growth hormone-releasing hormone (GHRH 1-29), the shortest portion of native 44-residue GHRH that retains full activity at the GHRH receptor. It was developed by EMD Serono and received two FDA approvals as Geref — a diagnostic indication in 1990 (NDA 19-863) and a therapeutic indication for pediatric idiopathic growth hormone deficiency in 1997 (NDA 20-443). EMD Serono voluntarily discontinued commercial production in 2008; the FDA determined in 2013 that the withdrawal was for commercial, not safety or efficacy, reasons. Sermorelin is currently available in the US only through state-licensed compounding pharmacies, which prescribe it off-label for adult indications that were never part of the original label. Among GHRH analogs it is unusual in having a formal FDA-approval history; CJC-1295 is a modified derivative of the same 1-29 fragment, and tesamorelin is a separately approved full-length analog.
Evidence map
| Evidence layer | Grade | What it supports |
|---|---|---|
| Human | Phase III / approved-label-era | Pediatric idiopathic growth hormone deficiency: pivotal trials supported the 1997 NDA 20-443 approval; Thorner 1996 (n=110, 12 months) reported boosted growth rates in 74% of children at 30 mcg/kg subcutaneous daily |
| Human (off-label adult) | Anecdotal / weak | No dedicated dose-ranging or efficacy RCT in healthy or aging adults is identified in available literature; adult use is described in compounding-pharmacy and anti-aging-clinic reports rather than controlled trials |
| Animal | Moderate | Source describes well-characterized GHRH-receptor pharmacology and supportive animal work (rodents, lambs, goats) for receptor activity and GH release; individual animal study results not separately extracted |
| In vitro | Moderate | Receptor pharmacology, signaling, and degradation studies (DPP-IV cleavage, mast-cell histamine release, adenylate cyclase activation) cited in source; individual assay results not separately extracted |
| Mechanism | Strong | GHRH-receptor agonism on pituitary somatotrophs is thoroughly characterized: receptor binding → adenylate cyclase / cAMP / PKA → GH synthesis and pulsatile release |
Claim check
| Claim | Verdict | Evidence layer | Confidence |
|---|---|---|---|
| Stimulates endogenous pulsatile GH release via the GHRH receptor | Supported (human, mechanism) | Human pediatric trials and pharmacology | High |
| Effective for pediatric idiopathic growth hormone deficiency at the historical Geref pediatric label regimen | Supported (human, pediatric only) | Human Phase III / approval-era | High |
| Currently FDA-approved | Contradicted | Regulatory record | High — Geref was withdrawn from the US market in 2008; the 2013 FDA determination addressed reasons for withdrawal, not reinstatement |
| Effective for adult anti-aging, body composition, or sleep at compounding-era doses | Not established | Human (anecdotal / off-label only) | Low — no controlled adult efficacy trial identified in source |
| Safer than exogenous recombinant HGH because pituitary feedback is preserved | Partially supported | Mechanism | Medium — pulsatility and somatostatin feedback are real mechanistic features, but downstream IGF-1 elevation carries the same theoretical long-term concerns as exogenous GH |
| Discontinued because of safety problems | Contradicted | Regulatory record | High — FDA 2013 Federal Register determination explicitly states withdrawal was not for safety or effectiveness |
| Permitted in competition because of historical FDA approval | Contradicted | WADA list | High — WADA S2 prohibits GHRH and analogs at all times regardless of approval status |
Human exposure studied
This section reports exposure used in the historical Geref label and in published human studies. It is not a personalized protocol.
| Context | Population | Exposure studied | Duration | Endpoint | Limitation |
|---|---|---|---|---|---|
| Historical FDA label (Geref therapeutic, NDA 20-443; withdrawn 2008) | Children with idiopathic growth hormone deficiency | 0.03 mg/kg (30 mcg/kg) subcutaneous once daily at bedtime | Continuous treatment with periodic reassessment of growth velocity | Linear growth / growth velocity | Pediatric indication only; brand product withdrawn 2008; not a current active label |
| Historical FDA label (Geref Diagnostic, NDA 19-863; 0.05 mg/amp; withdrawn) | Patients undergoing pituitary GH-reserve testing | Single IV bolus dose; GH measured at baseline and every 15 min for 1 hour | Single test session | Pituitary GH response | Diagnostic context only; product withdrawn |
| Pediatric clinical trial — Thorner et al. 1996, GHRH(1-29) in GH-deficient children, | Children with growth hormone deficiency (n≈110 referenced) | 30 mcg/kg subcutaneous once daily | 12 months | Growth-velocity response (74% responders within 6 months reported) | Pediatric population; predates modern rhGH-dominant standard of care |
| Adult off-label compounding-pharmacy use | Adults seeking anti-aging, body-composition, or sleep effects | Exact regimen not individually extracted; source describes a range of compounding-pharmacy regimens but no controlled adult dose-ranging trial | Not established in controlled trial | No validated adult efficacy endpoint | Off-label; no controlled adult efficacy trial identified in source; compounded preparations are not FDA-reviewed |
Safety signals
| Signal | Evidence context | Notes |
|---|---|---|
| Injection-site reactions | Historical Geref label / human clinical experience | Mild, commonly reported |
| Facial flushing | Historical Geref label / human clinical experience | Transient, related to GHRH-pathway activation |
| Headache | Historical Geref label / human clinical experience | Occasional |
| Dizziness; altered sense of taste | Historical Geref label / human clinical experience | Reported in approval-era safety data |
| Caution in epilepsy and untreated hypothyroidism | Original Geref labeling | Source describes labeling-era cautions |
| Caution in obesity, hyperglycemia, or elevated plasma fatty acids | Original Geref labeling | Source describes blunted GH response and metabolic context |
| IGF-1 elevation as downstream pharmacology | Mechanism / pediatric label context | Theoretical long-term concerns parallel those of exogenous GH; long-term comparative endpoint trials are not attached |
| Long-term adult safety at off-label doses | Not established | No long-duration controlled adult safety dataset is identified in available literature |
Label-era contraindications described in available literature include active or recent-history malignancy, pregnancy (Geref was Pregnancy Category C), breastfeeding (excretion not characterized), uncontrolled diabetes or insulin resistance, uncontrolled hypothyroidism, active acromegaly or pituitary adenoma, severe obesity (efficacy may be reduced), and hypersensitivity to sermorelin or label excipients (historical Geref used mannitol). Drug interactions described in available literature include glucocorticoids (blunt somatotroph response), somatostatin analogs such as octreotide and lanreotide (directly antagonize GHRH signaling), and thyroid status (uncorrected hypothyroidism reduces GH response). These are described as approval-era label and source context, not as clinical management instructions.
Regulatory status
| Region / body | Status | Notes |
|---|---|---|
| US (FDA) | Not currently approved as a commercial product | Geref (NDA 19-863 diagnostic, 1990; NDA 20-443 pediatric therapeutic, 1997) was voluntarily withdrawn by EMD Serono in 2008; NDA approvals formally withdrawn effective June 18, 2009. The 2013 Federal Register determination (78 FR 14095-14096) found the withdrawal was not for reasons of safety or effectiveness. No active FDA approval exists as of 2026. |
| US (compounding) | Available through state-licensed compounding pharmacies under individualized prescription for off-label adult use | Compounded preparations are not FDA-reviewed. The FDA's ongoing 503A bulk-substance review has created uncertainty about long-term compounding-pharmacy access; current status should be verified against current FDA lists. |
| EU (EMA) / UK (MHRA) | No current approval identified | Source describes sermorelin as treated as an unapproved drug for adult wellness indications across most EU member states. |
| Canada | No current approval identified | Source describes sermorelin as treated as an unapproved drug for adult wellness indications. |
| Australia (TGA) | Schedule 4 (prescription-only) classification of GH secretagogues and GHRH analogs | Source describes class-level scheduling. |
| WADA | Prohibited at all times (class S2: peptide hormones, growth factors, related substances and mimetics) | Per source-cited 2026 Prohibited List; LC-MS/MS detection methods exist and athlete sanctions for sermorelin use are described. Prior FDA approval does not exempt the compound from WADA prohibition. |
Clinical trials
| Trial / source | Phase | Population | Endpoint | Status / result |
|---|---|---|---|---|
| Geref pediatric pivotal trials supporting NDA 20-443 (pre-1997) | Phase III / pivotal | Children with idiopathic growth hormone deficiency | Linear growth / growth velocity | Completed; supported FDA approval in September 1997 |
| Thorner et al. 1996, "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), | Clinical trial (pediatric) | Children with growth hormone deficiency | Growth-rate response over 12 months | Completed; reported 74% response within 6 months at 30 mcg/kg/day |
| GRF(1-29) human pharmacology and pituitary-response studies (;) | Randomized controlled trial (pharmacology) | Adult subjects (acromegaly and other pharmacology contexts) | GH response under cholinergic / dopaminergic / TRH manipulation | Published pharmacology results |
| GRF(1-29)NH2 effects on short-term memory in healthy young subjects, | Clinical trial | Healthy young adults | Short-term memory neuroendocrine endpoints | Published; small exploratory study |
| Adult-GHD efficacy program | Not identified | Adults with documented or suspected adult-onset GH insufficiency | Adult efficacy endpoint | published literature explicitly states no published, peer-reviewed adult-GHD efficacy RCT of sermorelin with NCT registration is identified; Walker 2006 is a review proposing adult use, not an RCT |
Trials are reported as described in the available literature. NCT identifiers were not provided in available literature for the historical pediatric program. Last checked: source date stamp February 2026; trial registry was not independently re-queried in this card-writing pass.
Mechanism
Sermorelin is a GHRH-receptor agonist on anterior-pituitary somatotrophs. Receptor activation engages adenylyl cyclase, raising intracellular cAMP and activating PKA signaling, which promotes both synthesis and pulsatile secretion of growth hormone. Because the peptide is rapidly cleared (plasma half-life on the order of about 6 minutes by the IV route, somewhat longer by the subcutaneous route, with degradation by DPP-IV and other peptidases), each administered dose produces a single transient GH pulse rather than sustained GHRH-receptor occupancy. The hypothalamic-pituitary feedback loop — in particular somatostatin-mediated negative feedback — remains operative, so the GH response is bounded by the pituitary's own regulatory architecture. The downstream pharmacology (GH → hepatic IGF-1) is the same downstream axis engaged by exogenous recombinant GH; what differs is the upstream stimulus and the preservation of pulsatility.
Chemistry
| Field | Value |
|---|---|
| Amino-acid sequence | YADAIFTNSYRKVLGQLSARKLLQDIMSR-NH2 |
| Length | 29 amino acids (GHRH 1-29) |
| Topology | Linear |
| Modification | C-terminal amide (-NH2) |
| Molecular weight | ~3357.9 g/mol (as reported in source; deterministic check from sequence consistent with reported value) |
| Molecular formula | C₁₄₉H₂₄₆N₄₄O₄₂S (note: source-printed formula contains an apparent transcription artifact in the hydrogen and oxygen counts; reported here from sequence-consistent reconstruction with the formula flagged for review against a primary chemistry source) |
| CAS number | 86168-78-7 |
| Salt form | Acetate (sermorelin acetate, as marketed historically as Geref) |
| Sequence confidence | Verified (sequence is consistently reported as the 1-29 N-terminal fragment of human GHRH across both source sections) |
| Formula confidence | Needs review (source formula appears to contain a typographic artifact) |
Open questions
- Modern adult efficacy: No dedicated adult-onset GHD or adult anti-aging efficacy RCT for sermorelin is identified in available literature. Establishing whether the pediatric pharmacology translates to a meaningful adult clinical endpoint is the central unresolved question.
- Long-term safety at off-label adult exposure: The FDA-approval-era safety dataset is pediatric and shorter-term. Long-duration safety in healthy or aging adults using compounding-era regimens is not characterized in the attached source.
- Pulsatility versus comparable IGF-1 exposure: Whether preservation of pulsatility translates to a different long-term safety margin compared with exogenous recombinant GH at matched IGF-1 exposure has not been tested in long-duration comparative endpoint trials.
- Compounding-pharmacy product variability: Active pharmaceutical ingredient purity and reconstitution practices vary across compounding pharmacies, and this quality-control variance is not well characterized in the published literature identified.
- 503A bulk-substance status: The FDA's ongoing 503A review introduces uncertainty about long-term compounding-pharmacy access for sermorelin. Current status should be re-verified against the current FDA list.
- Modern head-to-head comparison with rhGH: Modern controlled head-to-head comparisons against current-standard recombinant GH in pediatric or adult GHD are limited.
- Combination use with GHRPs: Sermorelin combined with a growth-hormone-releasing peptide (e.g., ipamorelin) has pharmacological rationale but no controlled human outcome data identified in available literature.
▸full evidence table2 metrics
| metric | value | tool |
|---|---|---|
| ipTM | 0.8681477904319763 | boltz-2 |
| ranking score | 0.7959436774253845 | boltz-2 |
▸structural qualityopenfold3
| metric | value | note |
|---|---|---|
| gpde | 0.561 | global PDE — lower = better |
| disorder | NaN | fraction disordered |
▸3-letter notation
▸recipeboltz-2 1.0
| parameter | value |
|---|---|
| model | boltz-2 1.0 |
| weights | — |
| hardware | nvidia_nim_api |
| mlx version | — |
| python | — |
| random seed | — |
| msa strategy | none |
| diffusion samples | 1 |
| runtime | — |
| predicted by | mlx@peptide |
| predicted at | 2026-04-24 |
▸citationbibtex
@peptide{pep04431,
sequence = {YADAIFTNSYRKVLGQLSARKLLQDIMSRQ},
target = {ghsr},
author = {peptidemodel},
year = {2026},
status = {bioassayed}
}