Ipamorelin vs Sermorelin: Growth Hormone Secretagogue Comparison

Quick Comparison Table

Mechanism of Action: Two Different Receptor Pathways

Ipamorelin: Ghrelin Receptor Agonist

Ipamorelin is a synthetic pentapeptide and selective agonist of the growth hormone secretagogue receptor (GHSR), also known as the ghrelin receptor. When administered, ipamorelin binds to GHSR on somatotroph cells in the anterior pituitary gland, directly stimulating growth hormone release. The peptide does not interact significantly with other hormone receptor systems.

Ipamorelin Signaling Pathway:

• Binds GHSR (ghrelin receptor) on pituitary somatotrophs
• Activates IP3/DAG second messenger cascade
• Stimulates GH release from somatotroph granules
• Minimal HPA axis or gonadotropin axis effects
• Effects are GH-selective and appetite-neutral (unlike ghrelin itself)

Sermorelin: GHRH Analog

Sermorelin is a 29-amino acid synthetic analog of growth hormone-releasing hormone (GHRH). It is structurally identical to the first 29 amino acids of endogenous GHRH and binds to GHRH receptors on somatotroph cells. When administered, sermorelin stimulates GH release through the classical GHRH-mediated mechanism. However, this pathway has broader neuroendocrine effects.

Sermorelin Signaling Pathway:

• Binds GHRH-R on pituitary somatotrophs
• Activates cAMP/PKA second messenger cascade
• Stimulates GH release and increases somatotroph sensitivity to GH-releasing signals
• Also activates GHRH receptors in hypothalamus and other tissues
• Stimulates ACTH and cortisol through HPA axis activation

GH Pulse Profile & Secretion Patterns

Ipamorelin GH Pulse Profile

Ipamorelin produces acute, dose-dependent GH pulses with rapid onset (15-30 minutes post-injection) and offset. Peak GH levels typically reach 5-15 ng/mL depending on dose and baseline GH status. The peptide's selectivity means GH release is not suppressed by somatostatin (unlike some GHRPs), allowing more natural pulsatile patterns.

• Onset: 15-30 minutes
• Peak GH: 30-60 minutes
• Duration: 2-3 hours
• Typical Peak Levels: 5-15 ng/mL (200mcg subcutaneous dose)
• Somatostatin Resistant: Not suppressed by endogenous somatostatin feedback

Sermorelin GH Pulse Profile

Sermorelin produces GH pulses through physiologic GHRH signaling, with onset typically 15-45 minutes post-injection. Peak GH levels are variable but generally 3-10 ng/mL depending on dose and endogenous GHRH tone. Sermorelin pulses are subject to physiologic somatostatin feedback, meaning GH suppression can occur if somatostatin levels are elevated.

• Onset: 15-45 minutes
• Peak GH: 45-90 minutes
• Duration: 3-4 hours
• Typical Peak Levels: 3-10 ng/mL (100mcg subcutaneous dose)
• Somatostatin Sensitive: GH release suppressed by elevated somatostatin (e.g., after meals)

Side Effect Profile Comparison

Detailed Side Effect Analysis

Cortisol Elevation

Ipamorelin: Minimal cortisol elevation. Being GH-selective through the ghrelin pathway, ipamorelin does not significantly activate the HPA axis. Most users report no measurable cortisol changes with standard dosing (200-300mcg).

Sermorelin: Moderate cortisol elevation. GHRH receptor activation in the hypothalamus stimulates CRH release, which activates the HPA axis and increases ACTH and cortisol by 20-40% with regular dosing. High-dose or chronic sermorelin can cause adrenal fatigue and suppressed cortisol after discontinuation.

Prolactin Elevation

Ipamorelin: Minimal prolactin elevation. GH-selective receptor activation avoids significant prolactin stimulation. Most users show no clinical prolactin changes.

Sermorelin: Moderate prolactin elevation. GHRH pathway activation can stimulate TRH (thyrotropin-releasing hormone) and increase prolactin. Some users report gynecomastia risk or lactation with high-dose chronic use, especially if combined with other GHRP peptides.

ACTH & HPA Axis Effects

Ipamorelin: No significant ACTH elevation. Does not activate the HPA axis.

Sermorelin: 30-50% ACTH elevation through hypothalamic CRH stimulation. Chronic use can dysregulate the HPA axis and cause adrenal insufficiency upon discontinuation in some users.

Stacking & Synergistic Combinations

Ipamorelin + Sermorelin Stack

Combining ipamorelin and sermorelin produces synergistic GH release because they activate different receptor pathways (GHSR + GHRH-R). The combination creates higher, more sustained GH pulses than either peptide alone.

Ipamorelin + Other GHRPs (GHRP-6, GHRP-2)

While ipamorelin can be stacked with other growth hormone-releasing peptides (GHRP-6, GHRP-2), this increases risk of prolactin elevation and desensitization. Most experts recommend ipamorelin + sermorelin rather than multiple GHRP peptides.

Sermorelin + GHRP-6 Stack (Hyperbolic Stack)

A classic sermorelin + GHRP-6 combination is effective but carries higher cortisol and prolactin elevation risk. This stack is less popular now as ipamorelin + sermorelin provides better selectivity and fewer side effects.

Stack Desensitization

Continuous peptide administration (especially stacks) can cause downregulation of receptors and reduced GH response over time. Most protocols incorporate "off-weeks" or cycling (e.g., 5 days on, 2 days off) to maintain receptor sensitivity. Ipamorelin appears less prone to desensitization than GHRP-6/GHRP-2 due to its selective GHSR activation and somatostatin resistance.

Dosing & Administration Protocols

Ipamorelin Dosing

• Standard Dose: 200-300mcg subcutaneous or intramuscular once daily
• Optimal Timing: Pre-workout (30 minutes before exercise) or pre-meal (30 minutes before food) to maximize GH response
• Frequency: Once daily for anti-aging; can be 2x daily (pre-workout + evening) for enhanced results
• Cycles: 5-6 days on, 1-2 days off to prevent receptor desensitization
• Long-term Use: Generally well-tolerated; some users report fatigue after 8-12 weeks continuous use (tolerance)

Sermorelin Dosing

• Standard Dose: 100-200mcg subcutaneous once daily (FDA-approved range 0.2-0.6mg daily for GHD)
• Optimal Timing: Bedtime injection (aligns with endogenous nocturnal GH surge); or early morning on empty stomach
• Frequency: Once daily is standard; may be increased to 2x daily for more pronounced results
• Cycles: Many protocols use 5 days on, 2 days off to reduce HPA axis stimulation and cortisol elevation
• Long-term Use: Beyond 3-6 months may cause HPA axis dysregulation; HPA axis support (licorice, phosphatidylserine) may be needed

Combined Stack Dosing

When stacking ipamorelin + sermorelin, typical protocols include:

• Morning: Ipamorelin 200-300mcg on empty stomach or pre-workout
• Evening: Sermorelin 100-200mcg at bedtime
• Cycles: 5-6 days per week of both peptides
• Duration: 8-16 week cycles with 4-week breaks to assess tolerance and allow natural GH axis recovery

Clinical Applications & Who Benefits from Each

Ipamorelin: Ideal For

• Anti-aging protocols: GH-selective effects without hormonal dysregulation
• Body composition: Muscle gain and fat loss without water retention
• Recovery optimization: Enhanced muscle repair and sleep quality without adrenal stress
• Athletes with cortisol sensitivity: Those concerned about HPA axis suppression or cortisol dysregulation
• Metabolic health: Improved insulin sensitivity and metabolic rate without cortisol excess
• Aesthetic results: Skin quality, collagen synthesis, and tissue repair

Sermorelin: Ideal For

• FDA-approved therapeutic use: Diagnosed GH deficiency (only approved peptide GH secretagogue)
• GH axis rehabilitation: Restoring endogenous GH production through GHRH pathway stimulation
• Diagnostic use: GH stimulation tests for GHD diagnosis (FDA indication)
• Combination therapy: Works well with ipamorelin or GHRP-6 for synergistic GH release
• Age-related GH decline: Physiologic restoration of GH in aging populations

Comparative Benefits Summary