What are the differences and recommendations for using sermorelin (Growth Hormone Releasing Hormone (GHRH) analogue) versus ipamorelin (Growth Hormone Secretagogue (GHS)) in a patient with diagnosed growth hormone deficiency?

Sermorelin vs Ipamorelin for Growth Hormone Deficiency

For patients with documented growth hormone deficiency, recombinant human growth hormone (rhGH) remains the gold standard treatment, not sermorelin or ipamorelin, as these growth hormone secretagogues lack robust evidence for clinical efficacy and are not FDA-approved for treating GH deficiency. 1

Critical Context: Neither Agent is Standard of Care

The available guidelines focus exclusively on recombinant human GH therapy for documented GH deficiency, with no recommendations supporting sermorelin or ipamorelin as primary treatments. 2

• Diagnosis must be established first through appropriate GH-stimulation tests using validated cut-points before considering any GH-related therapy 1
• Persistent growth failure must be documented (height below 3rd percentile AND height velocity below 25th percentile for ≥3 months in infants or ≥6 months in older children) 1

Sermorelin: Limited Evidence Base

Mechanism: GHRH analogue (29 amino acids) that directly stimulates pituitary GH release 3

Diagnostic Use

• Sermorelin 1 mcg/kg IV is validated as a provocative test for GH deficiency diagnosis 3
• Produces fewer false positives compared to other provocative tests 3
• Critical limitation: Normal GH response to sermorelin cannot exclude hypothalamic GH deficiency 3

Therapeutic Use (Not Standard)

• Limited data shows 30 mcg/kg subcutaneous daily at bedtime increased height velocity in some prepubertal children with idiopathic GHD over 12 months 3
• Inferior to rhGH: When compared indirectly, sermorelin produced smaller increases in height velocity than standard rhGH dosing (30 mcg/kg/day) 3
• Long-term effects on final adult height remain undetermined 3
• Well-tolerated with transient facial flushing and injection site pain as most common adverse events 3

Limitations in Adults

• In normal aging adults, GHRH increased lean body mass but did not consistently improve physical function 4
• Effects on sleep and cognitive performance were inconsistent 4

Ipamorelin: Primarily Research Tool

Mechanism: Growth hormone secretagogue (ghrelin mimetic) that acts through GHS receptor 5

Key Concerns

• Paradoxical adiposity increase: Ipamorelin increased body fat in both GH-deficient and GH-intact mice through GH-independent mechanisms 6
• Increased serum leptin and food intake in animal models 6
• In rats, ipamorelin dose-dependently increased longitudinal bone growth rate (42 to 52 mcm/day at 450 mcg/day) 7
• No established clinical efficacy data in humans with GH deficiency

Mechanistic Differences from Sermorelin

• GHRH (sermorelin) and ghrelin-mimetics (ipamorelin) act synergistically when given together in vivo but only additively in vitro 5
• Ipamorelin acts through phospholipase C pathway (increasing intracellular calcium), while GHRH acts through adenylyl cyclase/cAMP pathway 5
• The Endocrine Society notes these different mechanisms should be considered when choosing between agents 8

Clinical Algorithm for GH Deficiency Treatment

Step 1: Confirm Diagnosis

• Perform validated GH stimulation testing with appropriate cut-points 1
• Document growth failure parameters (height <3rd percentile, velocity <25th percentile) 2

Step 2: Use FDA-Approved Recombinant Human GH

• Dosing: 0.045-0.05 mg/kg/day subcutaneous in evening 9
• This is the only treatment with established efficacy for morbidity, mortality, and quality of life outcomes 2

Step 3: Monitoring Requirements

• IGF-1 levels every 3-6 months 8, 9
• Glucose metabolism (insulin sensitivity concerns) 8, 9
• Growth parameters, thyroid function, calcium, phosphate, PTH 9
• Fundoscopy at baseline and if headache/vomiting develops (intracranial hypertension risk) 9

Critical Contraindications (Apply to All GH-Stimulating Agents)

Absolute contraindications: 2, 9

• Closed epiphyses
• Active malignancy
• Acute critical illness
• Known hypersensitivity
• Uncontrolled diabetes mellitus
• Pre-existing papilledema

Relative contraindications: 2

• Severe secondary hyperparathyroidism (PTH >500 pg/mL)
• Proliferative or severe non-proliferative diabetic retinopathy

Bottom Line

Neither sermorelin nor ipamorelin should replace recombinant human GH for treating documented GH deficiency. Sermorelin has limited evidence as a second-line option in select pediatric cases but is inferior to rhGH 3, while ipamorelin lacks human efficacy data and raises concerns about adiposity 6. The choice between these agents is moot—use FDA-approved rhGH unless there are compelling contraindications. 2, 1, 9