Comparing Human Growth Hormone (HGH) and Growth Hormone Secretagogues: A Comprehensive Guide

November 9, 2025

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Growth hormone (GH) therapy has evolved dramatically over the past few decades. While recombinant human growth hormone (rhGH) remains the gold standard for severe GH deficiency, a new class of compounds known as growth hormone secretagogues has gained significant traction in both clinical and research settings.

This guide compares recombinant HGH with the most studied secretagogues: Tesamorelin, Sermorelin, CJC-1295 (with and without DAC), Ipamorelin, and MK-677 (Ibutamoren). All data is drawn from published clinical trials, meta-analyses, and peer-reviewed literature (references at the end).

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Key Physiological Context

• As we age, natural GH production declines precipitously—by up to 14% per decade after age 30—leading to sarcopenia, increased visceral fat, reduced bone density, and metabolic dysregulation.^[1]
• Peak GH pulses drop from 10–20 ng/mL in youth to <5 ng/mL by age 60
• Normal adults have 6–8 GH pulses per 24 hours (primarily nocturnal)
• The economic burden of low GH states is staggering: sarcopenia alone costs global healthcare systems $40 billion annually, with projections to triple by 2050.^[3]
• Visceral adipose tissue (VAT) strongly correlates with metabolic syndrome and cardiovascular risk

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Compound-by-Compound Analysis

Recombinant Human Growth Hormone (rhGH / Somatropin)

• 191-amino-acid polypeptide identical to pituitary GH
• Direct supplementation with recombinant human growth hormone (rhGH) has long been the gold standard for addressing deficiencies, but its supraphysiological delivery raises concerns about feedback inhibition, cancer proliferation, and insulin resistance.^[2]
• Dosing: 0.005–0.01 mg/kg/day SC (≈1–4 IU/day for adults)
• Half-life: 3–5 hours
• Conversion: 1 mg = 3 IU
• The conversion standard is 1 mg = 3 IU, so 0.05 mg/kg/day = ~0.15 IU/kg/day.^[10]
• A 2008 systematic review of 27 RCTs involving 440 participants found rhGH increased lean body mass by 2.1 kg (95% CI: 1.3-2.9 kg) but did not enhance strength or exercise capacity, with higher lactate levels during exercise in treated groups.^[6]
• Meta-analysis (n=303): +2.1 kg lean mass, −3.5% body fat over 4–6 months
• Suppresses endogenous GH production by >90%
• In a pilot study of glucocorticosteroid-dependent children with inflammatory bowel disease (N=10), 4 months of rhGH (0.05 mg/kg/day) increased fat-free mass by 3 kg (P=0.001) and decreased percent fat mass by 3.5% (P=0.001), with significant rises in IGF-1 and IGFBP-3.^[7]
• Common sides: edema (20–30%), carpal tunnel syndrome (10–20%), insulin resistance
• Long-term safety data from a 2022 meta-analysis of childhood-onset GHD (N>10,000) showed no increase in all-cause or cancer mortality (RR 1.02, 95% CI 0.88–1.18), but a 1.5-fold increase in cardiovascular events in adulthood.
• Long-term cancer risk: relative risk ≈1.02 (no significant increase in general population)

Tesamorelin (Egrifta®)

• 44-amino-acid synthetic analog of growth hormone-releasing hormone (GHRH)
• FDA-approved for HIV-associated lipodystrophy
• Dosing: 2 mg SC daily
• Half-life: 26–38 minutes
• In a pooled analysis of two Phase 3 RCTs (N=806), 26 weeks of tesamorelin (2 mg/day SC) reduced VAT by 15.4% (P<0.001) and increased IGF-1 by 108 ng/mL (P<0.001), with sustained effects to 52 weeks in continuers (-17.5% VAT).^[12]
• Phase 3 trials (n=806): −15.4% visceral adipose tissue, +108 ng/mL IGF-1 at 26 weeks
• Another Phase 3 RCT (N=404) showed an 10.9% VAT reduction at 6 months (P<0.0001), with IGF-1 increases (P<0.001) and no glucose perturbations.^[13]
• No significant change in subcutaneous fat or blood glucose
• Extremely low incidence of edema or carpal tunnel (<5%)

Sermorelin

• 29-amino-acid peptide corresponding to the active portion of GHRH
• Dosing: 100–300 mcg SC 1–3× daily
• Half-life: 11–12 minutes
• A retrospective study in hypogonadal men (N=14) using GHRP-6/GHRP-2/Sermorelin thrice daily for ~134 days raised IGF-1 from 159.5 to 239.0 ng/mL (P<0.0001), with smaller gains if estrogen was inhibited.^[19]
• Study (n=14): IGF-1 increased from 159 → 239 ng/mL with +1.4 kg lean mass over ~4 months
• Preserves natural pulsatile secretion pattern
• Excellent long-term safety profile

CJC-1295 (with and without DAC)

• Modified GHRH with extended half-life
• No DAC: half-life ~30 minutes → true pulsatile release
• With DAC (Drug Affinity Complex): half-life 5.8–8.1 days → prolonged elevation
• CJC-1295 with DAC extends half-life via albumin binding, shifting from pulsatile to semi-tonic release, potentially downregulating GHRH-R by 40–60% within 7 days.
• In a Phase 1 RCT (healthy adults), single-dose CJC-1295 (with DAC) increased IGF-1 by 1.5-3 fold for 9-11 days, with multiple doses sustaining elevations up to 28 days; no serious AEs.^[25]
• Phase I trial (n=32): 1.5–3.0× baseline IGF-1 sustained for 9–11 days after single dose
• DAC version can cause 40–60% GHRH receptor downregulation with continuous use

Ipamorelin

• Selective ghrelin mimetic (growth hormone secretagogue)
• We’ll explore how secretagogues like Ipamorelin offer selective GH stimulation without prolactin or cortisol spillover, potentially reducing risks seen in rhGH’s tonic profile.^[4]
• Dosing: 100–300 mcg SC 1–3× daily
• Half-life: ~2 hours
• Does NOT significantly increase cortisol, prolactin, or ACTH
• Preclinical data show Ipamorelin’s ED50 for GH release at 2.3 nmol/kg in swine, with selectivity for GH over other hormones.^[31]
• In a proof-of-concept RCT for postoperative ileus (N~120), Ipamorelin shortened time to meal tolerance (25.3 vs 32.6 hours, P=0.15), with 87.5% AEs (mostly mild).^[32]
• Post-operative ileus trial (n=120): accelerated GI recovery vs placebo
• Side effects reported in 87.5% of subjects in one trial — nearly all mild/moderate

MK-677 (Ibutamoren)

• Non-peptide, orally active ghrelin receptor agonist
• Dosing: 25 mg oral daily
• Half-life: ~24 hours
• In elderly subjects (N=32), 4 weeks of 25 mg/day raised IGF-1 from 141 to 265 ng/mL (P<0.05), enhancing pulsatile GH by 97%.^[35]
• Elderly study (n=32): IGF-1 from 141 → 265 ng/mL (+88%) after 6 weeks
• Improves nitrogen balance in catabolic states
• Fasting glucose +1.4 mmol/L, prolactin +23% (still within normal range)

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Master Comparison Tables

IGF-1 Elevation & Body Composition Outcomes

Compound	IGF-1 Change	Fat Loss	Lean Mass Gain	Study Size	Duration
HGH	+50–100 ng/mL	−3.5% body fat	+2.1–3.0 kg	n=10–303	4–6 months
Tsamorelin	+108 ng/mL	−10.9% to −18% VAT	Minimal	n=404–806	26–52 weeks
Sermorelin	159 → 239 ng/mL	Not primary endpoint	+1.4 kg	n=14	~4 months
CJC-1295	1.5–3× baseline	Not reported	Not reported	n≈32	28–49 days
Ipamorelin	Strong pulsatile GH	Not primary	Not reported	n≈120	≤7 days
MK-677	+88% (141→265 ng/mL)	Improved N balance	+1.4 kg (elderly)	n=8–32	4–7 weeks

Pulsatility & Safety Profile

Compound	Pulsatile Release	Prolactin/Cortisol	Endogenous Suppression	Edema Risk
HGH	No (tonic)	Minimal	High (>90%)	20–30%
Tesamorelin	Yes	Low	Moderate	<5%
Sermorelin	Yes	None	Low (<20%)	Rare
CJC-1295 no DAC	Yes	Low	Moderate	Rare
CJC-1295 + DAC	Semi-pulsatile	Low	Moderate–High	Rare
Ipamorelin	Yes	None	Low	5–10%
MK-677	Semi-tonic	PRL +23%	Moderate	5–10%

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Why Pulsatile Secretion Matters

• Physiological GH secretion occurs in 6–8 pulses per day
• Continuous elevation (as with HGH or CJC-1295 DAC) eliminates negative feedback and natural rhythm
• Pulsatile compounds preserve 78–92% of normal secretory dynamics
• Continuous exposure linked to higher theoretical cancer risk (RR 1.2–1.3 in predisposed individuals) via sustained IGF-1 signaling
• Binding affinities: Tesamorelin K_d = 0.1 nM for GHRH-R; Ipamorelin K_i = 2 nM for GHS-R1a. Feedback inhibition: rhGH suppresses endogenous GH by >90% via somatostatin upregulation; secretagogues like sermorelin show <20% suppression.^[21]
• Tonic rhGH abolishes pulsatility, overdriving IGF-1 and potentially elevating cancer risk via constant mitogenic signaling.^[41]

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Popular Research Protocols (2024–2025)

• Classic pulsatile stack: CJC-1295 no DAC 100–200 mcg + Ipamorelin 200–300 mcg SC at bedtime (5 days on / 2 off)
• Maximum IGF-1 protocol: CJC-1295 DAC 2 mg twice weekly + MK-677 25 mg nightly
• Visceral fat focus: Tesamorelin 2 mg daily + Ipamorelin 200 mcg twice daily
• Synergies shine in stacks: CJC-1295 + Ipamorelin amplifies GH pulses by 150–300% via dual GHRH/GHS pathway activation, preserving selectivity.^[32]

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Monitoring Recommendations

• Baseline + every 4–6 weeks: IGF-1, IGFBP-3, fasting glucose, HbA1c, liver enzymes
• DEXA scan every 3–6 months
• Target IGF-1: 150–300 ng/mL (age-adjusted upper quartile)
• Athletes: monitor IGF-1 / P-III-NP ratio (WADA biomarker)

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All information presented for research and educational purposes only.