Sermorelin

Sermorelin is the amidated 29 residue fragment of growth hormone releasing hormone. It stimulates the pituitary to release growth hormone (GH) and was developed for evaluating GH secretion and promoting growth in selected children with GH deficiency. Its clinical literature includes increased childhood growth velocity, a direct comparison favoring GH treatment, an unsuccessful nasal formulation and a small adult HIV lipodystrophy trial. These results show how the pituitary's capacity to respond and the way the peptide is delivered shape its effects.

Overview

The first 29 amino acids of the natural releasing hormone preserve substantial GH releasing activity. Sermorelin contains that sequence with an amidated C terminus, the chemical modification indicated by GHRH(1–29)-NH2. Historical Geref products supplied sermorelin acetate. The sequence differs from modified GRF(1–29), which replaces four residues, and from the albumin binding CJC-1295 DAC molecule.

Molecular profile

Peptide length: 29 amino acid residues Source
Sequence identity: Natural first 29 residues of human GHRH Source
C terminal modification: Amide, written GHRH(1–29)-NH2 Source
Historical pharmaceutical form: Sermorelin acetate in Geref products Source

Forms and derivatives

Geref

Historical sermorelin acetate diagnostic and therapeutic products. Their approvals were withdrawn effective in 2009; FDA later determined that their withdrawal from sale was not for safety or effectiveness reasons.

D-Ala2-GHRH(1–29)-amide

A singly substituted analogue tested alongside the natural fragment in ten healthy men. Its reported mean disappearance half-time was 6.7 minutes, compared with 4.3 minutes for the natural amidated fragment.

Investigational nasal formulation

The nasal pilot showed early hormone responses that diminished, no increase in six month height velocity and frequent local symptoms.

Geref is the historical pharmaceutical name for sermorelin acetate. FDA's 2013 Federal Register determination describes discontinued therapeutic and diagnostic products and the withdrawal of their approvals effective in 2009. FDA subsequently determined that they had not been withdrawn from sale for reasons of safety or effectiveness. This history establishes what happened to those products; it does not establish approval for adult rejuvenation uses or for a newly compounded preparation.

Uses and research areas

The major clinical question was whether supplying a releasing signal could improve growth in children whose pituitary retained the capacity to produce GH. Investigators measured height velocity, hormone responses and biochemical safety. Studies in children with hypothalamic GH deficiency were especially relevant because the missing signal arose upstream from the pituitary.

An adult trial also examined the reduced GH secretion and altered body composition associated with HIV lipodystrophy. The study used Geref and followed IGF-1, lean mass and regional fat. Adult strength, functional recovery and aging outcomes require different measurements and are not established by the childhood growth studies or by an acute rise in GH.

Mechanism of action

The hypothalamus normally sends releasing hormone to the anterior pituitary, where specialized cells synthesize and release GH. Sermorelin stimulates the releasing hormone receptor on these cells. The resulting GH acts on tissues directly and promotes insulin-like growth factor 1 (IGF-1) production. A response therefore depends on a functioning pituitary and on the broader hormonal regulation of secretion. Losa and colleagues (1984) demonstrated acute activity of the 29 residue fragment in five healthy volunteers, with GH peaks occurring 15–30 minutes after intravenous administration.

That relationship between signal and response helps explain differences among patient groups. Tuilpakov and colleagues (1995) compared releasing hormone, GHRP-2 and their combination in ten children with GH insufficiency and five with idiopathic short stature. Acute GH responses were substantially larger in the latter group. The diagnostic context changed the response to stimulation, which is one reason a hormone challenge cannot by itself predict sustained growth or an adult clinical benefit.

Pharmacokinetics

GHRH(1–29)-amide disappearance illustrated after intravenous infusion

Population: Ten healthy human men. Administration: Intravenous infusion; disappearance phase after infusion ends. Analyte: Assayed infused GHRH(1–29)-NH2, represented as normalized modeled concentration C/C0; distinct from GH.

This calculated line uses the 4.3 minute mean disappearance half-time reported by Soule, King and Millar (1994) after intravenous infusion in ten healthy men. During the modeled phase, the concentration falls by half every 4.3 minutes. The reported standard error of the mean is 1.4 minutes. The line begins at 100% after infusion and follows C/C0 = 2^(-t/4.3), with time in minutes. It assumes a constant disappearance rate and shows the mean estimate without an uncertainty band or subcutaneous absorption phase.

Soule S, King JA, Millar RP. Soule et al. 1994 abstract Methods and Results: ten men, ninety minute infusion and twenty minutes of postinfusion sampling.

Soule, King and Millar (1994) measured infused GHRH(1–29)-amide and a separate D-Ala2 analogue in ten healthy men. After a 90 minute intravenous infusion, the reported disappearance half-time for the unmodified amidated fragment was 4.3 ± 1.4 minutes, expressed as mean ± standard error. The D-Ala2 analogue had a longer value of 6.7 ± 0.5 minutes. Replacing a single residue was already sufficient to alter clearance; four substituted residues and an added DAC unit define further distinct preparations.

The figure illustrates the unmodified fragment's reported mean, beginning at a normalized 100% when infusion has stopped. It calculates C/C0 = 2^(-t/4.3), with time in minutes, and assumes a constant disappearance half-time during that phase. The curve does not reproduce individual measurements or absorption after a subcutaneous administration. The source assayed the infused peptide, so its half-time describes peptide disappearance. The subsequent GH response has a separate time course, while height velocity reflects months of biology and must be evaluated independently.

Research findings

Childhood growth with subcutaneous preparations

Thorner and colleagues (1996), for the Geref International Study Group, treated 110 previously untreated prepubertal children with GH deficiency in a multicentre open label study; 86 were eligible for the efficacy analysis. Mean height velocity rose from 4.1 cm per year before treatment to 8.0 after six months and 7.2 after twelve months. The investigators reported no adverse biochemical or hormonal changes, including fasting glucose. The absence of a concurrent control and selection of the efficacy population limit how precisely the treatment effect can be separated from other influences on growth.

Brain, Hindmarsh and Brook (1990) examined continuous subcutaneous exposure in eight children with partial GH insufficiency. Five completed a year, with mean growth velocity increasing from 4.6 to 7.0 cm per year; three had shorter observations. GH pulses were augmented, and growth rates returned to pretreatment levels after cessation. The study provides a longitudinal response and withdrawal observation in a very small group.

Comparison with GH and a failed nasal formulation

Chen and colleagues (1993) randomized 60 children with GH deficiency of hypothalamic origin among two releasing hormone exposure groups and a direct GH group. At six months, mean height velocities were 9.2 and 9.3 cm per year in the fragment groups and 14.6 in the GH group. GH produced significantly more growth. IGF-1 initially rose with the fragment and subsequently returned toward pretreatment values. Antibodies developed in 39 of the 40 fragment recipients, without a detected relationship to height gain.

Hümmelink and colleagues (1993) tested a nasal formulation in eight short children who retained a GH response to intravenous releasing hormone. Early hormone peaks diminished over time. Six month height velocity did not increase, three children developed antibodies, and most reported nasal irritation or rhinorrhea. Two stopped early. The delivery route and formulation therefore changed both sustained exposure and the practical result, even though the underlying peptide was a GH releasing fragment.

Geref in adults with HIV lipodystrophy

Koutkia and colleagues (2004) randomized 31 men with HIV lipodystrophy to Geref or placebo for twelve weeks; 29 completed the study. Mean IGF-1 increased by 104 ng/mL with the fragment and 6 ng/mL with placebo. Lean mass changed by +0.9 versus −0.3 kg, and trunk fat by −0.4 versus +0.2 kg. Visceral fat fell in the Geref group and rose slightly with placebo, but the difference was too uncertain to establish an effect in this small trial (P = 0.07). Glucose, insulin and lipid changes were also not significant. The original JAMA report identifies Geref. This small adult study preceded tesamorelin's clinical program and supplies separate evidence for the shorter fragment.

Analytical metabolism research

Memdouh and colleagues (2021) studied how sermorelin and related analogues broke down in laboratory systems. They also added known amounts of peptide to urine to test how the parent and breakdown products could be detected and distinguished. These samples tested an analytical method; they did not come from an additional group of treated patients or provide clinical follow-up.

Safety and tolerability

The childhood studies reported generally acceptable short term biochemical monitoring, but antibodies and local reactions varied with preparation and delivery. Chen and colleagues found antibodies in nearly all fragment recipients and mild injection site irritation in three; Hümmelink and colleagues observed declining nasal tolerability and early discontinuations. Neither result supplies a reliable estimate of harms during prolonged adult use.

Geref's historical approval and FDA's finding about its discontinuation are sometimes used to imply current endorsement of broad adult hormone treatment. The FDA determination concerns the specific discontinued products. FDA also explains that compounded drugs are not FDA approved. Their preparation quality and present indications require their own assessment. The studies summarized here do not establish long term safety for adult anti-aging or performance use.

What the research means

The clinical work shows that a short releasing hormone fragment can raise GH and increase growth velocity when the pituitary can respond. The strongest comparative childhood study also found greater growth with direct GH, while the nasal pilot illustrates how early endocrine activity can fail to become sustained growth. These observations give a fuller account than treating every GH increase as equivalent.

The small adult HIV trial supports further study of body composition but leaves visceral fat efficacy uncertain. The broader unresolved questions are lasting clinical benefit, final adult height in the childhood programs, and safety over longer exposure. Answers depend on the particular preparation, diagnosis and outcome being measured.

FAQs

Was sermorelin previously approved?

Historical Geref products contained sermorelin acetate. The FDA determination (2013) records discontinuation, withdrawal of approvals in 2009, and the later finding that withdrawal from sale was not for safety or effectiveness reasons. Those statements concern the particular products and their historical indications.

Did it increase childhood growth?

Selected children with GH deficiency grew faster during several fragment studies. Thorner and colleagues (1996) reported increased height velocity in their eligible efficacy population. The randomized Chen comparison (1993) found greater growth with direct GH. Diagnosis, pituitary response and the comparator affect the conclusion.

What did the adult HIV trial show?

Koutkia and colleagues (2004) compared Geref with placebo for twelve weeks in men with HIV lipodystrophy, an alteration in fat distribution. IGF-1 rose more, lean mass increased more and trunk fat decreased more with Geref. The comparison of fat around the abdominal organs, called visceral fat, was too uncertain to establish a difference (P = 0.07). The small population and short follow-up leave broader adult benefits unresolved.

What is the peptide half-life?

Soule, King and Millar (1994) reported a 4.3 minute mean disappearance half-time with standard error of 1.4 minutes after intravenous infusion of GHRH(1–29)-amide in ten healthy men. It describes the assayed peptide in that context. Subcutaneous absorption and the GH response require separate measurements.

Is modified GRF another name for sermorelin?

Modified GRF(1–29) replaces four residues in the fragment. Sermorelin retains the natural sequence with terminal amidation. These chemical differences can change metabolism and require distinct evidence for exposure and clinical outcomes.

Did nasal delivery sustain growth?

The Hümmelink pilot (1993) found diminishing hormone peaks and no increase in six month height velocity. Nasal symptoms were common and two of eight children stopped early. Early endocrine activity therefore did not establish sustained success for that delivery formulation.

Sermorelin preserves the natural first 29 residues with an amidated end. Tesamorelin modifies the full length releasing hormone and has randomized visceral fat trials supporting an approved adult HIV indication. Modified GRF(1–29) changes four residues, and CJC-1295 with DAC adds an albumin binding unit to that modified core. Their distinct chemistry and development programs explain why one compound's half-life or clinical results cannot serve as another's evidence.

References

Losa M, Schopohl J, Müller OA, von Werder K. Stimulation of growth hormone secretion with human growth hormone releasing factors (GRF1-44, GRF1-40, GRF1-29) in normal subjects. Klinische Wochenschrift. 1984;62(23):1140-1143. DOI: 10.1007/BF01782473. PMID: 6240568.
A healthy volunteer comparison demonstrated acute GH releasing activity of three fragment lengths, including GRF(1-29).
Thorner M, Rochiccioli P, Colle M, Lanes R, Grunt J, Galazka A, Landy H, Eengrand P, Shah S. 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. The Journal of clinical endocrinology and metabolism. 1996;81(3):1189–1196. DOI: 10.1210/jcem.81.3.8772599. PMID: 8772599.
An open label childhood GH deficiency study reported increased height velocity in its eligible efficacy population.
Brain CE, Hindmarsh PC, Brook CG. Continuous subcutaneous GHRH(1-29)NH2 promotes growth over 1 year in short, slowly growing children. Clinical endocrinology. 1990;32(2):153–163. DOI: 10.1111/j.1365-2265.1990.tb00851.x. PMID: 2140733.
Eight children with partial GH insufficiency underwent continuous subcutaneous exposure and growth observations after cessation.
Chen RG, Shen YN, Yei J, Wang CF, Xie DH, Wang XH, Zhou JD, Chen CY, Wu YL, Gunnarsson R. A comparative study of growth hormone (GH) and GH-releasing hormone(1-29)-NH2 for stimulation of growth in children with GH deficiency. Acta paediatrica (Oslo, Norway : 1992). Supplement. 1993;388:32–36. DOI: 10.1111/j.1651-2227.1993.tb12834.x. PMID: 8329830.
A randomized childhood comparison found more growth with direct GH than with either fragment group; antibodies were common in fragment recipients.
Hümmelink R, Sippell WG, Benoit KG, Danielson K, Faijerson Y. Intranasal administration of growth hormone-releasing hormone(1-29)-NH2 in children with growth hormone deficiency: effects on growth hormone secretion and growth. Acta paediatrica (Oslo, Norway : 1992). Supplement. 1993;388:23–27. DOI: 10.1111/j.1651-2227.1993.tb12830.x. PMID: 8329828.
The nasal pilot found waning hormone responses, no increase in six month height velocity, local reactions and early withdrawals.
Tuilpakov AN, Bulatov AA, Peterkova VA, Elizarova GP, Volevodz NN, Bowers CY. Growth hormone (GH)-releasing effects of synthetic peptide GH-releasing peptide-2 and GH-releasing hormone (1-29NH2) in children with GH insufficiency and idiopathic short stature. Metabolism: clinical and experimental. 1995;44(9):1199–1204. DOI: 10.1016/0026-0495(95)90016-0. PMID: 7666796.
Acute hormone stimulation comparisons examined GH insufficiency and idiopathic short stature as separate childhood diagnostic groups.
Koutkia P, Canavan B, Breu J, Torriani M, Kissko J, Grinspoon S. Growth hormone-releasing hormone in HIV-infected men with lipodystrophy: a randomized controlled trial. JAMA. 2004;292(2):210–218. DOI: 10.1001/jama.292.2.210. PMID: 15249570.
A small randomized Geref trial in men with HIV measured IGF-1 and body composition; the visceral fat comparison was not statistically significant.
Memdouh S, Gavrilović I, Ng K, Cowan D, Abbate V. Advances in the detection of growth hormone releasing hormone synthetic analogs. Drug testing and analysis. 2021;13(11-12):1871–1887. DOI: 10.1002/dta.3183. PMID: 34665524.
The investigators studied peptide breakdown in laboratory systems and added known amounts to urine to test detection methods. They distinguished sermorelin, tesamorelin and CJC-1295 preparations with and without DAC.
Soule S, King JA, Millar RP. Incorporation of D-Ala2 in growth hormone-releasing hormone-(1-29)-NH2 increases the half-life and decreases metabolic clearance in normal men. The Journal of Clinical Endocrinology and Metabolism. 1994;79(4):1208-1211. DOI: 10.1210/jcem.79.4.7962295. PMID: 7962295.
Primary pharmacokinetics measured disappearance half-times of the natural amidated fragment and its singly substituted D-Ala2 analogue in ten men.
U.S. Food and Drug Administration. Determination That Geref Injection Products Were Not Withdrawn From Sale for Reasons of Safety or Effectiveness. Federal Register. 2013;78:14095-14096.
Official determination describes discontinued Geref products and their approval withdrawal, alongside the safety and effectiveness finding.
U.S. Food and Drug Administration. Understanding the Risks of Compounded Drugs. Accessed 13 October 2026.
FDA explains the approval and quality review status of compounded products.
Koutkia P, Canavan B, Breu J, Torriani M, Kissko J, Grinspoon S. Growth hormone-releasing hormone in HIV-infected men with lipodystrophy: a randomized controlled trial. JAMA. 2004;292(2):210-218. DOI: 10.1001/jama.292.2.210.
Original article identifies Geref and clarifies enrollment and follow-up.

Glossary

GHRH: Growth hormone releasing hormone, a hypothalamic peptide that stimulates GH producing pituitary cells.
IGF-1: Insulin-like growth factor 1, produced in liver and other tissues and mediating part of the GH response.
Pharmacokinetics: The study of how a compound enters, moves through and leaves the body.
Half-life: Time for an assayed concentration to fall by half during a specified disappearance or elimination phase.
Amidation: A chemical modification at the end of a peptide chain, indicated by NH2 in these names.
Height velocity: Rate of height increase, often expressed in centimetres per year.
Standard error: An estimate of uncertainty around a mean, distinct from the spread of individual observations.
GH deficiency: Insufficient GH production or secretion.
Lipodystrophy: Altered fat distribution, including regional loss and accumulation.