Are there peptides supported by data to increase growth hormone (GH) levels?

Growth Hormone-Stimulating Peptides: Evidence-Based Overview

Yes, there are specific peptides with robust data demonstrating growth hormone (GH) elevation, primarily recombinant human growth hormone (somatropin) itself and growth hormone-releasing peptides (GHRPs), though their clinical applications and evidence quality differ substantially.

Recombinant Human Growth Hormone (Somatropin)

Somatropin is the gold standard peptide with the strongest evidence for increasing GH levels and achieving clinically meaningful outcomes in approved indications. 1

Mechanism and Efficacy

• Somatropin is bioidentical to endogenous GH with 191 amino acids, binding to dimeric GH receptors and triggering intracellular signaling that increases IGF-1 production 1
• Absolute bioavailability after subcutaneous administration is 81 ± 20% in healthy adults, with a terminal half-life of 2.1 ± 0.43 hours subcutaneously 1
• In pediatric patients with GH deficiency or chronic kidney disease (CKD), somatropin increases height velocity by a mean of 3.88 cm per year (95% CI 3.32–4.44) compared to untreated controls 2

Clinical Applications with Strong Evidence

• Pediatric GH deficiency: Meta-analysis of 16 RCTs with 809 patients demonstrated increased height standard deviation score (SDS) of 0.91 (95% CI 0.58–1.23) after 1 year of treatment 2
• CKD-related growth failure: Supraphysiological doses overcome GH insensitivity in CKD by stimulating IGF-1 synthesis and promoting longitudinal growth 2
• Post-Cushing disease remission: Early GH replacement in proven GH-deficient children enables catch-up growth and normalization of lean-to-adipose mass ratio 2

Monitoring Requirements

• Height measurements quarterly to detect declining growth velocity 3
• IGF-1 levels every 6 months to maintain physiologic range and avoid supraphysiological dosing 3
• Annual bone age radiographs to monitor for impending epiphyseal closure 3
• Treatment discontinuation when height velocity drops below 2 cm per year, indicating approaching epiphyseal closure 2, 3

Growth Hormone-Releasing Peptides (GHRPs)

GHRPs represent a class of synthetic peptides with documented GH-releasing activity, but their clinical utility remains primarily investigational with limited FDA approval for routine use.

GHRP-6 and Related Hexapeptides

• GHRP-6 demonstrates potent GH stimulation via specific receptors at both pituitary and hypothalamic levels, with no structural homology to GHRH 4, 5
• The GH-releasing effect is dose-related and reproducible after intravenous, subcutaneous, intranasal, and oral administration 4, 5
• Combined administration of GHRH plus GHRP-6 (1 microgram/kg IV each) elicited significant GH increases in approximately 40% of adults diagnosed with GH deficiency by conventional testing 6

GHRP-1 (Heptapeptide)

• GHRP-1 administered as IV bolus (1 microgram/kg) to healthy short children produced progressive GH rise peaking at 15-30 minutes, with significantly higher responses in pubertal versus prepubertal subjects 7
• Six of eight hypopituitary patients showed no response to GHRP-1, indicating limited efficacy in true pituitary insufficiency 7

Mechanism of Action

• GHRPs likely act by counteracting somatostatinergic activity at both pituitary and hypothalamic levels, possibly via GHRH-mediated mechanisms 4, 5
• The GHRP receptor has been cloned but shows no sequence homology with other known G-protein-coupled receptors, suggesting existence of an undiscovered natural ligand 4, 5, 8
• GH-releasing activity is synergistic with GHRH and only partially blunted by inhibitory influences that nearly abolish GHRH effects 5, 8

Clinical Limitations

• Inconsistent efficacy: GHRPs show reduced effectiveness in idiopathic GH deficiency, obesity, hypothyroidism, and almost absent responses in pituitary stalk disconnection or Cushing's syndrome 4, 5
• Lack of regulatory approval: Despite marked GH-releasing effects, GHRPs remain primarily research tools without widespread FDA approval for clinical GH replacement 4, 5
• Age-related variations: GHRP activity increases from birth to puberty, persists in adulthood, but decreases significantly by the sixth decade, though remaining higher than GHRH activity 4

Non-Peptidyl GH Secretagogues

• MK-0677 represents the most promising non-peptidyl GHRP mimetic with demonstrated effects in animals and humans, acting via GHRP receptors with oral bioavailability 4, 5
• These compounds maintain GH-releasing activity even after oral administration, offering potential therapeutic advantages over injectable peptides 4

Critical Clinical Considerations

When Somatropin Should NOT Be Used

• Active malignancy or evidence of tumor progression 2
• Acute critical illness or complications following open heart surgery, abdominal surgery, or multiple trauma 1
• Acute respiratory failure 1
• Diabetic retinopathy 1
• Closed epiphyses in pediatric patients 2

Metabolic Monitoring

• Somatropin may decrease insulin sensitivity, requiring glucose metabolism monitoring, particularly in overweight or obese individuals 1
• Fasting and postprandial insulin levels typically increase during treatment, though glucose and HbA1c generally remain in normal range 1

Alternative Considerations for GH Stimulation

• Growth hormone plus glutamine: Conflicting results in short bowel syndrome with growth-hormone-related side effects affecting quality of life; not recommended for routine use 2
• Androgens: Insufficient consistent data to recommend currently approved androgenic steroids for increasing muscle mass in cachexia 2
• Cannabis derivatives (dronabinol): Limited and inconsistent evidence does not support recommendation for appetite stimulation in cancer cachexia 2

Bottom Line for Clinical Practice

For legitimate medical indications (pediatric GH deficiency, CKD-related growth failure, Turner syndrome), recombinant human somatropin is the only peptide with robust evidence demonstrating both GH elevation and clinically meaningful improvements in morbidity and quality of life. 2, 1 GHRPs remain investigational with documented GH-releasing activity but lack the comprehensive safety and efficacy data required for routine clinical use outside research protocols. 6, 4, 5 The choice between tesamorelin and ipamorelin should consider their different mechanisms of action and potential side effects when used in approved contexts. 9