What are the therapeutic uses and precautions for peptides, such as growth hormone-releasing peptides (GHRPs), in medical treatment?

Therapeutic Uses and Precautions for Peptides in Medical Treatment

Growth Hormone and Growth Hormone-Releasing Peptides (GHRPs)

Growth hormone-releasing peptides are potent synthetic stimulators of GH secretion that act through specific receptors distinct from GHRH receptors, with marked efficacy in pubertal children and adults but limited utility in prepubertal children and elderly patients. 1, 2

Established Therapeutic Applications

Growth Hormone Therapy in Children

• Administer GH at 0.045-0.05 mg/kg body weight per day via subcutaneous evening injections to mimic physiological circadian rhythm 3, 4
• Both reference GH products and biosimilars are equally recommended, with comprehensive pharmacovigilance data over 10 years showing no relevant safety differences 3, 4
• Primary indications include:
  • Growth hormone deficiency with persistent growth failure (height below 3rd percentile and growth velocity below 25th percentile) 4
  • Children with chronic kidney disease and growth impairment 3
  • Height between 3rd-10th percentile with persistently low growth velocity after addressing other treatable causes 4

GHRPs as GH Secretagogues

• GHRPs demonstrate dose-related GH release after intravenous, subcutaneous, intranasal, and oral administration, with oral bioavailability representing a significant clinical advantage 1, 5
• The GH-releasing effect is synergistic with GHRH and more resistant to inhibitory influences (somatostatin, glucose, free fatty acids) compared to GHRH alone 1
• Peak efficacy occurs in pubertal children and young adults, with substantially reduced responses in prepubertal children and elderly subjects 2

Acromegaly Management

• For patients not responding to somatostatin receptor ligand (SRL) therapy, switch to pegvisomant treatment 3
• For partial responders to SRL therapy, consider combination therapy with pegvisomant and SRL 3
• Dose escalation of cabergoline from 1.5 to 3.5 mg per week if well tolerated for dopamine agonist therapy 3

Critical Monitoring Requirements

Schedule clinic visits every 3-6 months to monitor multiple parameters, with more frequent visits for young patients and those with advanced disease 3, 4:

• Height, growth velocity, and pubertal development (Tanner staging) 3, 6, 4
• Skeletal maturation via wrist radiography 3, 4
• Thyroid function (TSH and free T3) 3, 4
• Glucose metabolism (serum glucose) 3, 4
• Calcium, phosphate, bicarbonate levels 3, 4
• Parathyroid hormone levels 3, 4
• Serum IGF-1 levels if growth velocity is inadequate 3, 4

Absolute Contraindications

Immediately discontinue GH therapy in the following situations 3, 4:

• Epiphyseal closure demonstrated on radiography 3, 4
• Persistent severe secondary hyperparathyroidism (PTH >500 pg/ml) - may reinstitute when PTH returns to target range 3, 4
• Intracranial hypertension - perform baseline fundoscopy before initiating therapy and immediate work-up if persistent headache or vomiting occurs 3, 4
• Slipped capital femoral epiphysis 3, 4
• Active malignancy 4
• Critical acute illness 4
• Known hypersensitivity to active substance or excipients 4

Important Precautions and Adverse Effects

Metabolic Complications

• Monitor glucose metabolism closely in obese patients due to increased risk of impaired glucose tolerance, though GH treatment ≤5 years typically does not adversely affect glucose tolerance 3
• Insulin secretion increases during first year with persistent hyperinsulinemia during long-term therapy 3
• Patients with nephropathic cystinosis have increased diabetes mellitus risk regardless of GH treatment 3

Bone and Mineral Metabolism

• Adequately treat chronic kidney disease-mineral bone disorder (CKD-MBD) before initiating GH therapy according to current guidelines 3
• GH may directly stimulate parathyroid glands or affect calcium/phosphate homeostasis, potentially unmasking pre-existing renal osteodystrophy 3
• Withhold therapy if PTH >500 pg/ml and reinstitute when levels normalize 3

Special Population Considerations

• Primary prophylaxis with G-CSF is contraindicated during chest chemoradiotherapy due to increased bone marrow suppression risk and complications 3
• In patients who can become pregnant at moderate/high fracture risk, PTH/PTHrP may be used if growth plates are closed 3
• PTH/PTHrP and romosozumab should only be used in adults with closed growth plates 3
• Denosumab should be used with caution in patients with open growth plates 3

Age-Related Response Variations

• GH response to GHRPs increases from birth to puberty, remains stable in adulthood, then decreases thereafter 1
• By the sixth decade, GHRP activity is reduced but still higher than GHRH response 1
• In pubertal children, GH response to hexarelin (67.6 ± 12.7 μg/L) exceeds that in prepubertal children (19.0 ± 4.6 μg/L) 2

Inadequate Response Management

If height velocity in first year is <2 cm/year above baseline, systematically assess 3, 4:

1. Patient adherence to therapy (including serum IGF-1 measurement) 3, 4
2. Weight-adjusted GH dosage accuracy 3, 4
3. Nutritional and metabolic factors 3, 4
4. Consider discontinuation if no adequate response despite optimal control 3, 4

Drug Delivery Applications

• Peptides are increasingly utilized for targeted drug delivery to specific cell types (cancer cells, immune cells) to reduce systemic side effects 7
• Peptides derived from intercellular junction proteins (occludins, claudins, cadherins) enhance drug delivery through intestinal mucosa barrier and blood-brain barrier via paracellular pathways 7
• These modulator peptides have demonstrated enhanced brain delivery of molecules ranging from small compounds to 65 kDa albumin 7

Common Pitfalls to Avoid

• Never administer GH immediately before or simultaneously with chemotherapy due to risk of worsening thrombocytopenia 3
• Change injection sites daily to prevent lipoatrophy 3, 4
• Do not target ANC >10 × 10⁹/L when using G-CSF - this is unnecessary 3
• Recognize that oral estrogens can reduce hepatic IGF-1 generation, potentially confounding test results 6
• IGF-1 may be falsely normal/low in patients with GH-secreting adenoma who have concurrent severe hypothyroidism, malnutrition, or severe infection 6