Sermorelin
GRF(1-29), GHRH(1-29)-NH2, sermorelin acetate, growth hormone-releasing factor 1-29
Sermorelin is the first 29 amino acids of human growth hormone-releasing hormone, the shortest fragment that retains the full activity of the natural hormone. It was the first GHRH analogue ever approved as a medicine, licensed in the US in 1990 as a diagnostic agent and in 1997 for treating growth hormone deficiency in children, before being discontinued in 2008 for commercial reasons and formally withdrawn in 2009. Today it is supplied almost entirely through compounding pharmacies for adult uses that were never studied and never approved.
Mechanism
Sermorelin is the identical N-terminal 29-residue sequence of endogenous human GHRH, amidated at the C-terminus. Native GHRH is 44 amino acids long, but the first 29 carry essentially all of the receptor-binding and activating information, a discovery that made a synthetically tractable GHRH drug possible. Sermorelin binds the GHRH receptor on pituitary somatotrophs, couples through Gs to adenylate cyclase, raises cAMP, and activates protein kinase A. The downstream consequences are twofold: immediate exocytosis of stored growth hormone granules, and, through CREB and the transcription factor POU1F1, sustained transcription of the GH1 gene together with maintenance of the somatotroph population itself.
Because sermorelin works through the pituitary rather than bypassing it, the resulting growth hormone secretion remains inside the body's own regulatory loop. Hypothalamic somatostatin still gates when secretion can occur, and IGF-1 generated by the liver still feeds back to restrain both the pituitary and the hypothalamus. In practice this means three things. Growth hormone output is capped by pituitary reserve, so an intact feedback system makes acromegalic overshoot far less likely than with exogenous growth hormone. Response requires a functioning pituitary, so sermorelin does nothing in someone whose deficiency is pituitary rather than hypothalamic in origin, which is precisely what makes it useful as a diagnostic probe. And its action is brief: the native sequence retains the dipeptidyl peptidase-4 cleavage site at the N-terminus that clips GHRH within minutes, which is why the entire modern class of GHRH analogues (modified GRF (1-29), CJC-1295, tesamorelin) consists of attempts to protect that same bond.
What the research shows
Sermorelin's genuine evidence base is paediatric. In a multicentre, open-label study, 110 previously untreated prepubertal children with growth hormone deficiency received 30 micrograms per kilogram per day of GHRH(1-29) subcutaneously at bedtime for up to a year; among the 86 children eligible for analysis, height velocity rose from 4.1 cm/year at baseline to 8.0 cm/year at six months and 7.2 cm/year at twelve months, and 74 per cent were classed as good responders at six months. As a diagnostic test, intravenous sermorelin at 1 microgram per kilogram proved rapid and relatively specific, generating fewer false-positive growth hormone responses in children without deficiency than the older provocative tests. That work supported the FDA approvals, and it is real. It is also worth being precise about what kind of evidence it is: the pivotal treatment study was open-label with no control group, and sermorelin was never shown in a head-to-head trial to match recombinant growth hormone for final adult height. It lost the paediatric market to recombinant growth hormone, and the manufacturer discontinued it in 2008. The FDA subsequently confirmed in a March 2013 Federal Register notice that the withdrawal was not for reasons of safety or effectiveness.
The adult evidence is much weaker, and it is the adult use that dominates supply today. Vittone and colleagues gave 2 mg of GRF(1-29) nightly by subcutaneous self-injection for six weeks to eleven healthy men aged 64 to 76 with low baseline IGF-1. Nocturnal growth hormone release and peak amplitude increased, and two of several strength measures (upright row and shoulder press) plus abdominal endurance improved, but IGF-1, IGFBP-3 and growth hormone binding protein did not change, and neither did weight, body mass index, waist-to-hip ratio or DEXA body composition. The authors concluded that single nightly dosing appeared less effective than multiple daily dosing. That is an open-label study of eleven men in which the central biomarker did not move. Beyond it there is very little: no adequately powered randomised trial has tested sermorelin in adults for body composition, sleep quality, recovery, cognition, or any of the outcomes for which it is now marketed as an 'anti-ageing' or 'growth hormone optimisation' therapy. The gap between what sermorelin was approved to do in children and what it is currently sold to do in adults is wide, and it is not bridged by evidence. Sermorelin's real distinction in this class is that it is the only short-acting GHRH fragment that has ever been through a genuine regulatory review at all.
Evidence assessment
Limited evidence
Downgraded from 'mixed' on audit: the pivotal paediatric treatment study was open-label and uncontrolled, the only cited adult study was open-label in eleven men and found no change in IGF-1 or body composition, and no placebo-controlled trial of sermorelin as treatment appears in the citation set at all. The former FDA approval, though genuine, is not itself controlled evidence.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
Once daily subcutaneous growth hormone-releasing hormone therapy accelerates growth in growth hormone-deficient children during the first year of therapy Limited evidence
Height velocity rose from 4.1 cm/year at baseline to 8.0 cm/year at six months and 7.2 cm/year at twelve months, with 74 per cent classed as good responders at six months; treatment was well tolerated.
Sermorelin: a review of its use in the diagnosis and treatment of children with idiopathic growth hormone deficiency Limited evidence
Intravenous sermorelin at 1 microgram/kg gave a rapid and relatively specific diagnostic test with fewer false positives than other provocative tests; once-daily subcutaneous treatment produced sustained height velocity increases in some prepubertal children.
Effects of single nightly injections of growth hormone-releasing hormone (GHRH 1-29) in healthy elderly men Limited evidence
Nocturnal GH release and peak amplitude increased, but IGF-1, IGFBP-3 and GH binding protein were unchanged, as were weight, BMI, waist-to-hip ratio and DEXA body composition; only two strength measures (upright row, shoulder press) and abdominal endurance improved, and the authors concluded single nightly dosing was less effective than multiple daily dosing.
Determination That GEREF (Sermorelin Acetate) Injection, 0.5 Milligrams Base/Vial and 1.0 Milligrams Base/Vial, and GEREF (Sermorelin Acetate) Injection, 0.05 Milligrams Base/Amp, Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness Limited evidence
FDA formally determined that the withdrawal of the approved sermorelin products, effective 18 June 2009 following the manufacturer's 2008 discontinuation, was not for reasons of safety or effectiveness.
Safety
Sermorelin has the longest human safety record of anything in this class, and it is reassuring as far as it goes. In paediatric use the common findings were injection-site pain, redness and swelling, with headache, flushing, dysphagia and dizziness reported less often. Antibodies to sermorelin were reported in a minority of children on long-term treatment in the historical prescribing information, generally without loss of response. Because it stimulates the pituitary rather than replacing growth hormone, the somatostatin and IGF-1 feedback loops remain intact, making sustained supraphysiological growth hormone exposure less likely than with recombinant growth hormone. Two important caveats apply. First, that safety record was accumulated in children with a diagnosed deficiency, under medical supervision, at defined doses, for defined durations, none of which describes the adult market that consumes sermorelin today, where long-term safety is genuinely unknown. Second, no approved sermorelin product exists anywhere, so every dose administered now comes from a compounded or unregulated preparation whose potency, purity, sterility and endotoxin content have not been verified by any regulator. The class hazards remain: fluid retention, arthralgia, carpal tunnel symptoms, worsened glucose tolerance, and a theoretical neoplasia concern from prolonged IGF-1 elevation.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | No current UK marketing authorisation. Supply for human use outside an authorised route is unlawful under the Human Medicines Regulations 2012. Where sermorelin is offered by UK clinics it is as an unlicensed medicine or an imported special, which shifts clinical and legal responsibility onto the prescriber. |
| United States | Formerly FDA-approved: as an intravenous diagnostic agent for growth hormone deficiency in 1990, and for treatment of idiopathic growth hormone deficiency with growth failure in children in 1997. The manufacturer notified FDA of discontinuation in 2008 and marketing approval was withdrawn effective 18 June 2009. A Federal Register determination published on 4 March 2013 confirmed the withdrawal was not for safety or effectiveness reasons, a finding whose formal purpose is to permit generic (ANDA) applications, and which is also commonly relied on to support continued compounding. Sermorelin is currently supplied in the US almost entirely by compounding pharmacies under FDA's interim policy on 503A bulk drug substances, a status that has been under active review and may change. There is no FDA-approved sermorelin product on the market today, and compounded sermorelin has not been reviewed by FDA for safety, effectiveness or manufacturing quality. |
| WADA (sport) | Prohibited at all times under section S2.2.4 of the WADA Prohibited List, which names sermorelin explicitly among prohibited GHRH analogues. |
Questions
Not any more. It was approved in 1990 as a diagnostic agent and in 1997 for treating growth hormone deficiency in children, but the manufacturer discontinued it in 2008 and the approval was withdrawn in June 2009. FDA confirmed in March 2013 that the withdrawal was commercial rather than for safety or effectiveness. Any sermorelin available today is a compounded preparation that has not been reviewed by FDA.
Commercial reasons, not safety. Recombinant human growth hormone came to dominate the paediatric growth hormone deficiency market (it works in a wider range of patients, including those whose pituitary cannot respond to GHRH), and sermorelin became commercially unviable for its sole manufacturer.
There is no adequate evidence that it does. The trials supporting sermorelin's approval were open-label studies in children with diagnosed growth hormone deficiency. In older adults, the published work amounts to small open studies such as Vittone's, in which eleven men had higher nocturnal growth hormone but no change in IGF-1 and no change in body composition. No adequately powered randomised trial has tested sermorelin in adults for body composition, sleep, recovery or cognition.
Sermorelin is the unmodified natural sequence and is cleared within minutes. CJC-1295 is the same fragment with four protective amino acid substitutions plus, in the DAC form, an albumin-binding linker that extends the half-life to about a week. Sermorelin also has something CJC-1295 does not: a genuine regulatory review and an approved clinical trial record, albeit open-label and in children.