GHRH

Also known as: GRF, Somatoliberin, GHRH(1-44)

Evidence: Clinical

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Overview

Native hypothalamic hormone (somatorelin, GHRH 1-44) that triggers GH release from pituitary somatotrophs; used clinically as a diagnostic GH-stimulation agent.

Growth hormone-releasing hormone (somatorelin, GRF) is the 44-residue hypothalamic peptide that drives pituitary GH secretion. It was isolated in 1982 from pancreatic tumors causing acromegaly (Guillemin 1982; Rivier 1982). Plasma dipeptidyl peptidase cleaves the N-terminal Tyr-Ala within minutes, leaving an inactive GHRH(3-44) (Frohman 1986). Its main clinical role is diagnostic: GHRH 1 mcg/kg IV plus arginine is a validated test for adult GH deficiency, with BMI-specific cut-offs (Aimaretti 1998; Corneli 2005). Nocturnal pulsatile SC GHRH(1-40) accelerated growth in 3 of 5 GH-deficient children (Smith 1986). The approved drugs built on it are the 1-29 fragment sermorelin and the stabilized 1-44 analog tesamorelin.

Benefits

GH release and pituitary reserve testing (human, GHRH-arginine test validated in hundreds of patients), growth acceleration in GH-deficient children with pulsatile dosing (human, n=5, open label), reference ligand for GH-axis research

Dosing reference

Research dose: 1 mcg/kg IV (diagnostic GHRH-arginine test, about 70-100 mcg); 1-2 mcg/kg per SC pulse in a pediatric treatment study; research-community range 100-200 mcg SC nightly
Range: 100 to 200 mcg, 1x daily
Reconstitution: 2 mL bacteriostatic water
Common vial sizes: 2 mg, 5 mg

Native GHRH(1-44). IV bolus in diagnostic testing; SC in the pediatric pulsatile study. Intact peptide disappears from plasma with a half-life of about 7 min, so each injection gives one brief GH pulse (Frohman 1986). Facial flushing lasting 1-3 min occurred in 16 of 18 men given 1 mcg/kg IV (Bowers 1990).

Mechanism

GHRH (Growth Hormone Releasing Hormone, also called GRF or somatoliberin) is a 44 amino acid peptide from the hypothalamus that stimulates GH secretion from pituitary somatotrophs. Binds to GHRH-R, a G-protein coupled receptor, activating adenylyl cyclase and cAMP production. This triggers calcium influx and GH granule exocytosis. Native GHRH has a very short half-life (~7-10 minutes) due to DPP-IV cleavage, necessitating development of more stable analogs like CJC-1295 and tesamorelin.

Evidence

Clinical: at least one published human trial or an approved drug

Isolated and sequenced from pancreatic tumors causing acromegaly (Guillemin et al., 1982; Rivier et al., 1982)
Plasma clearance 194 L/m2/day; elimination-phase half-life of immunoreactive GRF 52 min after IV injection in men (Frohman et al., 1984)
Intact GHRH(1-44) half-life 6.8 min in vivo; cleaved to inactive GHRH(3-44) by a plasma dipeptidylaminopeptidase (Frohman et al., 1986)
Nocturnal pulsatile SC GHRH(1-40) raised growth velocity from 3.7 to 7.2 cm/year in 3 of 5 GH-deficient children (Smith et al., 1986)
GHRH + arginine test is as sensitive as insulin hypoglycemia for adult GH deficiency, with BMI-specific cut-offs from 640 subjects (Aimaretti et al., 1998; Corneli et al., 2005)
Human-trial status: used clinically as a diagnostic stimulus; the approved therapeutics are its analogs sermorelin (1997) and tesamorelin (2010)

References

Side effects

Transient facial flushing (1-3 min) in 16 of 18 men after 1 mcg/kg IV (Bowers 1990). No adverse effects reported in the pediatric pulsatile study (Smith 1986). Injection-site redness, headache, water retention, joint aches and reduced insulin sensitivity are commonly reported (anecdotal) with sustained GH elevation.

Storage

Storage: Refrigerate 2-8°C (36-46°F)
Lyophilized: 2+ years at room temp, 3+ years refrigerated
Reconstituted: 28-30 days refrigerated

Pharmacology

Half-life: ~7 min for intact GHRH(1-44) (human, IV; HPLC, Frohman 1986); immunoreactive elimination phase ~52 min (human, IV; Frohman 1984)
Molecular weight: 5040.4 Da
Sequence: YADAIFTNSYRKVLGQLSARKLLQDIMSRQQGESNQERGARARL[NH2]