A Deep Dive into Growth Hormone Secretagogues: Clinical Evidence, Mechanisms, and Therapeutic Applications
Growth hormone secretagogues represent a revolutionary approach to enhancing human growth hormone production through targeted stimulation of the body's natural regulatory pathways. This comprehensive analysis examines the clinical evidence, regulatory landscape, and practical applications of key peptides including sermorelin, tesamorelin, GHRP-2, GHRP-6, ipamorelin, and ibutamoren (MK-677).
The Physiological Foundation: Understanding Growth Hormone Regulation
The hypothalamic-pituitary axis orchestrates growth hormone release through a sophisticated interplay of stimulatory and inhibitory signals. Growth Hormone Releasing Hormone (GHRH), produced by the hypothalamus, stimulates both GH synthesis and release while binding to GHRH receptors in the pituitary[1]. This peptide increases both the number of somatotropes and the amount of GH secreted from each cell, with no downregulation observed[1].
Conversely, somatostatin (also known as Growth Hormone Inhibiting Hormone) provides negative feedback by inhibiting GH synthesis and release, making the hypothalamus resistant to stimulation and responsible for pulsatile GH inhibition[1]. Critically, somatostatin levels increase with age, contributing to the natural decline in GH production observed in aging populations[1].
The ghrelin pathway represents a distinct mechanism from GHRH, binding to GHRP receptors (ghrelin receptors) in the pituitary to release GH while simultaneously reducing somatostatin inhibition and stimulating GHRH production from the hypothalamus[1]. This dual mechanism creates "artificial amplification" that works synergistically with endogenous GHRH[1].
Sermorelin: The GHRH Analog Pioneer
Clinical Efficacy and Pharmacokinetics
Sermorelin (Geref), an analog containing the first 29 amino acids of natural GHRH, demonstrates robust clinical efficacy with a 12-minute half-life when administered intravenously or subcutaneously[1]. Clinical trials show that 74% of children experienced increased growth rates after just 6 months of daily sermorelin injections[2]. In adults, sermorelin increases hGH levels in the bloodstream and may enhance general well-being, lean body mass, insulin sensitivity, and libido, though definitive anti-aging research remains limited[2].
Unique Physiological Advantages
Sermorelin offers several key advantages over direct growth hormone replacement. The peptide upregulates its own receptor, promotes non-REM slow wave sleep, and creates episodic rather than constant tissue exposure to GH, preventing tachyphylaxis by mimicking normal physiology[3][1]. By stimulating pituitary gene transcription of hGH messenger RNA, sermorelin increases pituitary reserve and preserves more of the growth hormone neuroendocrine axis[3].
Safety Profile and Dosing
Human studies consistently demonstrate excellent tolerability, with sermorelin being generally well-tolerated with few serious adverse events[2][3]. Recommended dosing ranges from 1,000-2,000 mcg subcutaneously at bedtime, with some protocols using up to 2,000 mcg total daily for weight loss and age management applications[1].
Tesamorelin: FDA-Approved Clinical Success
Regulatory Approval and Clinical Applications
Tesamorelin represents the pinnacle of growth hormone secretagogue clinical validation, holding FDA approval since November 2010 for reducing excess abdominal fat in HIV-infected patients with lipodystrophy[4][5]. This distinction makes it the only FDA-approved treatment for lipodystrophy and demonstrates the clinical viability of GH secretagogue therapy[4].
Clinical Trial Evidence
Two pivotal clinical trials involving 816 HIV-positive adults with lipodystrophy demonstrated tesamorelin's efficacy. Among 543 patients receiving active treatment during the 26-week placebo-controlled period, tesamorelin produced 15-17% reductions in abdominal fat measured by CT scan compared to placebo[4]. The most recent FDA approval of EGRIFTA WR (tesamorelin F8) in March 2025 provides weekly reconstitution convenience while maintaining bioequivalence to the original formulation[6][7].
Safety and Tolerability
The safety profile of tesamorelin is well-established through extensive clinical use in Japan, where it maintains approval as a diagnostic agent for GH deficiency[8]. Common adverse reactions include arthralgia, injection site reactions, pain in extremity, peripheral edema, and myalgia, with particular attention to potential effects on blood sugar control[4][6].
Growth Hormone Releasing Peptides: The Ghrelin Mimetics
GHRP-6: The Potent Pioneer
GHRP-6 demonstrates significant clinical efficacy as a potent stimulator of GH secretion across multiple species, including humans[9]. Clinical trials show dose-dependent GH increases with peak responses occurring 45 minutes after administration and returning to baseline by 210 minutes[10]. Pharmacokinetic studies in healthy volunteers reveal biphasic kinetics with a rapid distribution phase (7.6-minute half-life) and elimination phase (2.5-hour half-life)[11]. The peptide produces dose-proportional plasma increases, making clinical dosing predictable[11].
GHRP-2: Superior Potency Profile
Human studies demonstrate that GHRP-2 stimulates GH release 2-3 times more effectively than GHRP-6[12][13]. In controlled studies of healthy males, GHRP-2 infusion (1 μg/kg/hour) produced a 35.9% increase in food intake compared to placebo, with peak GH levels reaching approximately 36 μg/L within 60 minutes[14]. A remarkable clinical case involved a severely emaciated anorexia nervosa patient who received intranasal GHRP-2 for one year, gaining 6.7 kg body weight while experiencing increased hunger, improved muscle strength, and prevention of severe hypoglycemic episodes with no reported side effects[8][15][16].
Side Effect Considerations
Both GHRP-6 and GHRP-2 increase prolactin and cortisol levels, significantly increase hunger and gastric emptying, making them particularly useful for weight gain protocols but potentially problematic for weight loss applications[1]. This contrasts sharply with ipamorelin's selective profile.
Ipamorelin: The Selective Advantage
Selectivity and Safety Profile
Ipamorelin represents the most selective growth hormone secretagogue, distinguished by its unique ability to stimulate GH release without significantly affecting cortisol, ACTH, or prolactin levels even at doses 200-fold higher than required for GH stimulation[17][18]. This selectivity translates to superior tolerability with clinical trials reporting only mild, transient symptoms including slight water retention, temporary flushing, and minimal appetite stimulation[19].
Pharmacokinetic Excellence
Comprehensive pharmacokinetic data from 40 healthy male volunteers across five dosing levels (4.21-140.45 nmol/kg) reveal dose-proportional kinetics with a terminal half-life of 2 hours, clearance of 0.078 L/h/kg, and volume of distribution of 0.22 L/kg[20][21]. GH stimulation demonstrates a single episode of release with peak concentrations at 0.67 hours[20].
Clinical Applications
Phase 2 randomized controlled trials focused on gastrointestinal applications, with 117 patients undergoing bowel resection surgery receiving ipamorelin (0.03 mg/kg twice daily) versus placebo for up to 7 days[22]. While primary efficacy endpoints showed modest results, ipamorelin demonstrated excellent tolerability with fewer adverse events than placebo (87.5% vs 94.8%)[22].
Ibutamoren (MK-677): The Oral Alternative
Pharmacological Profile
Ibutamoren offers unique advantages as an orally active, selective agonist of the ghrelin receptor with a 24-hour half-life[1]. This long duration allows once-daily dosing at 25 mg, providing sustained GH stimulation without injection requirements[1].
Clinical Evidence and Limitations
A comprehensive 12-month study in 65 healthy adults aged 60-81 years demonstrated sustained increases in pulsatile GH secretion and fat-free mass[23]. However, significant safety concerns emerged when a clinical trial examining MK-677 for hip fracture recovery in elderly patients was stopped early due to increased rates of congestive heart failure (6.5% vs 1.7% in placebo group)[18][24]. The FDA subsequently listed ibutamoren as posing "significant safety risks due to the potential for congestive heart failure in certain patients"[24].
Regulatory Status and Warnings
Despite its research potential, MK-677 remains unapproved for human consumption and appears on the DoD Prohibited Dietary Supplement Ingredients List and WADA Prohibited List[24]. Long-term safety concerns include potential increases in fasting blood glucose, hyperglycemia risk, and negative impacts on bone mineral density[24].
Hexarelin and CJC-1295: Extended Duration Compounds
Hexarelin Clinical Data
Hexarelin demonstrates substantial dose-dependent GH release in human subjects, with peak concentrations occurring at 30 minutes and returning to baseline within 240 minutes[25][26]. Clinical studies show ED50 values of 0.50-0.64 μg/kg, with effects after 2 μg/kg doses approaching maximal response[25]. However, chronic hexarelin therapy results in partial and reversible attenuation of GH response, with biological impact on the GH-IGF-1 axis being minimal during extended use[27].
CJC-1295: Long-Acting GHRH Analog
CJC-1295, a GHRH analog with albumin-binding properties, demonstrates remarkable pharmacokinetics with a half-life of 5.8-8.1 days[28][29]. Single injections produce dose-dependent increases in plasma GH concentrations by 2-10-fold for 6 days or more, with IGF-1 levels increasing 1.5-3-fold for 9-11 days[28]. Multiple doses maintain elevated IGF-1 levels for up to 28 days with preserved GH pulsatility[29][30].
Clinical Protocol Applications and Dosing Strategies
Weight Loss and Age Management Protocols
For weight loss and age management applications, sermorelin monotherapy typically employs 1,000 mcg subcutaneously at bedtime, increasing up to 2,000 mcg total daily based on IGF-1 responses[1]. Maintenance protocols often utilize 1,000 mcg three times weekly once therapeutic levels are achieved[1].
Combination Therapy Approaches
Sermorelin/ipamorelin combinations (500/500 mcg subcutaneously at bedtime) provide enhanced GH release compared to sermorelin alone while avoiding the hunger and hormonal side effects associated with GHRP-2 and GHRP-6[1]. This combination can be increased to 2,000 mcg total daily depending on IGF-1 laboratory results[1].
Weight Gain and Anabolic Protocols
For patients requiring weight gain and maximum GH response, GHRP-2/GHRP-6/sermorelin combinations (667/200/500 mcg subcutaneously before meals or twice/three times daily) provide the most significant hunger increase and anabolic stimulus[1].
Safety Considerations and Contraindications
Universal Contraindications
All growth hormone secretagogues share common contraindications including pregnancy, active malignancy, history of malignancy, diabetic proliferative retinopathy, sclerosing diseases of the liver and lungs, benign intracranial hypertension, and uncontrolled diabetes[1].
Timeline for Clinical Benefits
Patients typically require at least 3 months of consistent therapy before experiencing benefits, with full therapeutic effects usually apparent by 6 months[1]. This extended timeline necessitates patient education and realistic expectation setting for optimal treatment outcomes.
Regulatory Landscape and Legal Considerations
Current FDA Status
The regulatory environment for growth hormone secretagogues varies significantly by compound and application. While tesamorelin maintains FDA approval for specific indications, most other peptides exist in a complex regulatory framework involving compounding pharmacy regulations under Section 503A of the Federal Food, Drug & Cosmetic Act[31][32].
Compounding Restrictions and Biologics Classification
The 2020 implementation of the Biologics Price Competition and Innovation Act reclassified many peptides as biologics (compounds with >40 amino acids), removing them from compounding eligibility[31][32]. Peptides with ≤40 amino acids remain potentially eligible for compounding if they meet specific criteria: appearing in FDA-approved products, having USP monographs, or being listed on the Section 503A Bulks List[32][33].
Off-Label Prescribing Considerations
Unlike recombinant human growth hormone, which has legal restrictions on clinical use, the off-label prescribing of compounds like sermorelin is not prohibited by federal law[3][1]. This distinction provides clinicians with greater flexibility in therapeutic applications while maintaining appropriate medical supervision.
Recent FDA Actions
The FDA has increased scrutiny of peptide compounding, placing several growth hormone secretagogues on Category 2 of the bulk substances list, indicating "significant safety risks"[34][35]. These actions reflect ongoing efforts to balance patient access with safety considerations in an evolving regulatory environment.
Future Directions and Clinical Implications
The clinical evidence supporting growth hormone secretagogues demonstrates their potential as safer alternatives to direct GH replacement therapy. Their ability to work within physiological feedback mechanisms, combined with extensive safety data from clinical trials, positions these compounds as valuable therapeutic tools for addressing age-related GH decline and specific medical conditions.
However, the evolving regulatory landscape requires careful navigation by healthcare providers and patients. The distinction between FDA-approved applications (such as tesamorelin for HIV lipodystrophy) and off-label uses necessitates informed clinical decision-making based on risk-benefit analyses and patient-specific factors.
The future of growth hormone secretagogue therapy likely depends on continued clinical research, regulatory clarification, and the development of standardized treatment protocols that maximize therapeutic benefits while minimizing potential risks. As our understanding of these compounds deepens, they may play increasingly important roles in age management, metabolic optimization, and specific disease treatment protocols.
References:
Peptide Information and Descriptions - Excel Male TRT Forum
Sermorelin Therapy Benefits, Risks, Uses, Approval, and Side Effects
Sermorelin: A better approach to management of adult-onset growth hormone insufficiency? - PMC
FDA approves tesamorelin for reduction of central fat accumulation | HIV i-Base
FDA Approves F8 Formulation of Theratechnologies' Tesamorelin for HIV-Associated Lipodystrophy
https://www.theratech.com/news-rele...eceives-fda-approval-egrifta-wrtm-tesamorelin
https://www.drugs.com/history/egrifta-wr.html
https://onlinelibrary.wiley.com/doi/full/10.1002/jcsm.12028
https://www.nature.com/articles/pr1994725
https://archive.hshsl.umaryland.edu/bitstreams/b11e0b7d-27cf-4e26-813d-2035f73c54f4/download
https://pubmed.ncbi.nlm.nih.gov/23099431/
https://www.sciencedirect.com/science/article/abs/pii/S0739724000000503
https://www.sciencedirect.com/science/article/abs/pii/S0196978197000168
https://pmc.ncbi.nlm.nih.gov/articles/PMC2824650/
https://pubmed.ncbi.nlm.nih.gov/26401470/
https://pmc.ncbi.nlm.nih.gov/articles/PMC4575555/
https://pubmed.ncbi.nlm.nih.gov/9849822/
https://pmc.ncbi.nlm.nih.gov/articles/PMC5632578/
https://swolverine.com/blogs/blog/i...imal-protocols-for-recovery-and-muscle-growth
https://pubmed.ncbi.nlm.nih.gov/10496658/
https://link.springer.com/article/10.1023/A:1018955126402
https://pubmed.ncbi.nlm.nih.gov/25331030/
https://pmc.ncbi.nlm.nih.gov/articles/PMC2757071/
https://www.opss.org/article/performance-enhancing-substance-mk-677-ibutamoren
https://link.springer.com/article/10.1007/BF00191904
https://pubmed.ncbi.nlm.nih.gov/7957536/
https://academic.oup.com/jcem/article-abstract/83/5/1644/2865542
https://pubmed.ncbi.nlm.nih.gov/16352683/
https://academic.oup.com/jcem/article/91/3/799/2843281
https://academic.oup.com/jcem/article/91/12/4792/2656274
https://newdrugloft.com/compounding-peptides-what-prescribers-should-know/
https://join.a4pc.org/hubfs/PDFs/2022-08-Prescriber-Briefing-Peptides_4-Aug-2022.pdf
https://www.frierlevitt.com/articles/regulatory-status-of-peptide-compounding-in-2025/
https://www.fda.gov/drugs/human-dru...pounding-may-present-significant-safety-risks
https://honehealth.com/edge/fda-peptide-ban/
Here is some basic information regarding the different GH secretagogues
Hormones involved and related analog drugs
•Growth Hormone Releasing Hormone:
1. Sermorelin
2. Tesamorelin
•Ghrelin:
1. GHRP
2. Ipamorelin
3. Ibutamoren
•Somatostatin
•Growth Hormone
1. Recumbent human growth hormone (rHGH)
•Insulin-Like Growth Factor-1
1. recumbent IGF-1
Growth Hormone Releasing Hormone (GHRH)
•Produced by hypothalamus
•Stimulates GH synthesis and RELEASE
•Binds to the GHRH-R in pituitary
•Short half-life ~12 min
•Increases # of somatotropes AND amount of GH secreted from each
•No down regulation of GH
Ghrelin
•Bind to GHRP-R (“Ghrelin receptor”) in pituitary to release GH
•Reduce inhibition by Somatostatin at pituitary
•Distinct and separate path than GHRH
•Stimulate GHRH production from hypothalamus
•Inhibit Somatostatin production from hypothalamus
Somatostatin (SS)
•“SS” aka Growth Hormone Inhibiting Hormone (GHIH) or Somatotropin Release-Inhibiting Factor (SRIF)
•Produced primarily by hypothalamus
•Inhibits GH synthesis and release
•Makes hypothalamus resistant to stimulation by GHRH and hypoglycemia
•Responsible for pulsatile GH inhibition
•Decreases number of somatotropes, not amount of GH production by each
•Increases with age
Sermorelin
•Geref—Sermorelin Acetate for Injection
•Analog of GHRH - First 29 amino acids
•Used for traditional GH stimulation testing
•T ½ 12 mins. IV or SC
•Up regulates own receptor
•Promotes non-REM slow wave sleep
•Dose: 1,000-2,000mcg SQ qhs
Growth Hormone Releasing Peptides (GHRP)
•Synthetic forms of Ghrelin
•GHRP-1, GHRP-2, GHRP-6, MK-0677,
Hexarelin, Ipamorelin, Ghrelin
•Simple, short-chained amino acid complexes
•Bind to GHRP-R GH
•“Artificial amplification” b/c works with endogenous GHRH
Sermorelin / GHRP-2 / GHRP-6
•Increases prolactin and cortisol
•Significantly increases hunger and gastric emptying
•Cost effective
•GHRPs will start a pulse, and acts synergistically with GHRPs, so there is no need to be concerned about administration timing if you co-administer GHRPs with Sermorelin.
•GHRPs Requires Endogenous Hypothalamic GHRH for Maximal GH Stimulation
–NAUSHIRA PANDYA, ROBERTA DEMOTT-FRIBERG, CYRIL Y. BOWERS, ARIEL L. BARKAN, AND CRAIG A. JAFFE, Journal of Clinical Endocrinology and Metabolism 1998 Vol. 83, No
•Dose: Recon with 7.5mL Bac Water, Inject 0.25mL SQ bid/tid
Sermorelin / Ipamorelin
•For higher GH release than Sermorelin alone
•Ipamorelin like GHRP-2 and GHRP-6, but does not induce hunger, prolactin or cortisol release
•Dose: 500/500mcg SQ qhs. Increase to 1,000/1,000mcg depending on IGF-1 lab results.
Ibutamoren
•Selective agonist of the ghrelin receptor
•Long acting (T ½ 24h)
•Orally active
•Studied in treatment of obesity, bone density and muscle mass
•Dose: 25mg po qd
rHGH vs GHRH / GHRP
•GHRH / GHRP significantly less expensive than rHGH
•HGH overdosing is minimized or completely avoided with GHRH / GHRP
•Tissue exposure to HGH released by the pituitary under the influence of GHRH / GHRP is episodic not “square wave”, preventing tachphylaxis by mimicking normal physiology
•By stimulating the pituitary, GHRH / GHRP preserves more of the growth hormone neuroendocrine axis which fails first during aging
•GHRH / GHRP blocks the cascade of hypophyseal hormone failure that occurs during aging, thereby preserving youthful anatomy and physiology
•GHRH / GHRP provides all the benefits of HGH replacement therapy and more, YET IT’S OFF LABEL USE IS NOT PROHIBITED BY FEDERAL LAW
Commonly Prescribed Protocols I have observed
•Sermorelin
–Weight Loss / Age Management (Inject 1,000 mcg SQ qhs)
–Increase up to 2,000 mcg total daily
–IGF-1 Maintenance protocol 1,000mcg tiw
•GHRP-2/GHRP-6/Sermorelin
–Weight gain and high GH Response (Inject 667/200/500mcg SQ before meals or bid/tid)
–Most significant hunger increase
•Sermorelin/Ipamorelin
–Weight Loss / Age Management / Lean Mass (Inject 500/500 mcg SQ qhs)
–Increase up to 2,000 mcg total daily
–IGF-1 Maintenance protocol 1,000mcg tiw
•Ibutamoren
–Age Management / Fat Loss / Lean Mass Increase (25mg po qd)
–No need for injections
–Long T ½
–Some patients will exhibit hunger
•Patients will not start exhibiting the benefits of GHRT until at least 3 months of being on their program and it usually takes about 6 months to see the full benefits of the therapy.
Contraindications
•Pregnancy
•Malignancy
•History of Malignancy
•Diabetic proliferative retinopathy
•Sclerosing diseases of the liver and lungs
•Benign intracranial hypertension
•Uncontrolled diabetes
Growth hormone secretagogues represent a revolutionary approach to enhancing human growth hormone production through targeted stimulation of the body's natural regulatory pathways. This comprehensive analysis examines the clinical evidence, regulatory landscape, and practical applications of key peptides including sermorelin, tesamorelin, GHRP-2, GHRP-6, ipamorelin, and ibutamoren (MK-677).
The Physiological Foundation: Understanding Growth Hormone Regulation
The hypothalamic-pituitary axis orchestrates growth hormone release through a sophisticated interplay of stimulatory and inhibitory signals. Growth Hormone Releasing Hormone (GHRH), produced by the hypothalamus, stimulates both GH synthesis and release while binding to GHRH receptors in the pituitary[1]. This peptide increases both the number of somatotropes and the amount of GH secreted from each cell, with no downregulation observed[1].
Conversely, somatostatin (also known as Growth Hormone Inhibiting Hormone) provides negative feedback by inhibiting GH synthesis and release, making the hypothalamus resistant to stimulation and responsible for pulsatile GH inhibition[1]. Critically, somatostatin levels increase with age, contributing to the natural decline in GH production observed in aging populations[1].
The ghrelin pathway represents a distinct mechanism from GHRH, binding to GHRP receptors (ghrelin receptors) in the pituitary to release GH while simultaneously reducing somatostatin inhibition and stimulating GHRH production from the hypothalamus[1]. This dual mechanism creates "artificial amplification" that works synergistically with endogenous GHRH[1].
Sermorelin: The GHRH Analog Pioneer
Clinical Efficacy and Pharmacokinetics
Sermorelin (Geref), an analog containing the first 29 amino acids of natural GHRH, demonstrates robust clinical efficacy with a 12-minute half-life when administered intravenously or subcutaneously[1]. Clinical trials show that 74% of children experienced increased growth rates after just 6 months of daily sermorelin injections[2]. In adults, sermorelin increases hGH levels in the bloodstream and may enhance general well-being, lean body mass, insulin sensitivity, and libido, though definitive anti-aging research remains limited[2].
Unique Physiological Advantages
Sermorelin offers several key advantages over direct growth hormone replacement. The peptide upregulates its own receptor, promotes non-REM slow wave sleep, and creates episodic rather than constant tissue exposure to GH, preventing tachyphylaxis by mimicking normal physiology[3][1]. By stimulating pituitary gene transcription of hGH messenger RNA, sermorelin increases pituitary reserve and preserves more of the growth hormone neuroendocrine axis[3].
Safety Profile and Dosing
Human studies consistently demonstrate excellent tolerability, with sermorelin being generally well-tolerated with few serious adverse events[2][3]. Recommended dosing ranges from 1,000-2,000 mcg subcutaneously at bedtime, with some protocols using up to 2,000 mcg total daily for weight loss and age management applications[1].
Tesamorelin: FDA-Approved Clinical Success
Regulatory Approval and Clinical Applications
Tesamorelin represents the pinnacle of growth hormone secretagogue clinical validation, holding FDA approval since November 2010 for reducing excess abdominal fat in HIV-infected patients with lipodystrophy[4][5]. This distinction makes it the only FDA-approved treatment for lipodystrophy and demonstrates the clinical viability of GH secretagogue therapy[4].
Clinical Trial Evidence
Two pivotal clinical trials involving 816 HIV-positive adults with lipodystrophy demonstrated tesamorelin's efficacy. Among 543 patients receiving active treatment during the 26-week placebo-controlled period, tesamorelin produced 15-17% reductions in abdominal fat measured by CT scan compared to placebo[4]. The most recent FDA approval of EGRIFTA WR (tesamorelin F8) in March 2025 provides weekly reconstitution convenience while maintaining bioequivalence to the original formulation[6][7].
Safety and Tolerability
The safety profile of tesamorelin is well-established through extensive clinical use in Japan, where it maintains approval as a diagnostic agent for GH deficiency[8]. Common adverse reactions include arthralgia, injection site reactions, pain in extremity, peripheral edema, and myalgia, with particular attention to potential effects on blood sugar control[4][6].
Growth Hormone Releasing Peptides: The Ghrelin Mimetics
GHRP-6: The Potent Pioneer
GHRP-6 demonstrates significant clinical efficacy as a potent stimulator of GH secretion across multiple species, including humans[9]. Clinical trials show dose-dependent GH increases with peak responses occurring 45 minutes after administration and returning to baseline by 210 minutes[10]. Pharmacokinetic studies in healthy volunteers reveal biphasic kinetics with a rapid distribution phase (7.6-minute half-life) and elimination phase (2.5-hour half-life)[11]. The peptide produces dose-proportional plasma increases, making clinical dosing predictable[11].
GHRP-2: Superior Potency Profile
Human studies demonstrate that GHRP-2 stimulates GH release 2-3 times more effectively than GHRP-6[12][13]. In controlled studies of healthy males, GHRP-2 infusion (1 μg/kg/hour) produced a 35.9% increase in food intake compared to placebo, with peak GH levels reaching approximately 36 μg/L within 60 minutes[14]. A remarkable clinical case involved a severely emaciated anorexia nervosa patient who received intranasal GHRP-2 for one year, gaining 6.7 kg body weight while experiencing increased hunger, improved muscle strength, and prevention of severe hypoglycemic episodes with no reported side effects[8][15][16].
Side Effect Considerations
Both GHRP-6 and GHRP-2 increase prolactin and cortisol levels, significantly increase hunger and gastric emptying, making them particularly useful for weight gain protocols but potentially problematic for weight loss applications[1]. This contrasts sharply with ipamorelin's selective profile.
Ipamorelin: The Selective Advantage
Selectivity and Safety Profile
Ipamorelin represents the most selective growth hormone secretagogue, distinguished by its unique ability to stimulate GH release without significantly affecting cortisol, ACTH, or prolactin levels even at doses 200-fold higher than required for GH stimulation[17][18]. This selectivity translates to superior tolerability with clinical trials reporting only mild, transient symptoms including slight water retention, temporary flushing, and minimal appetite stimulation[19].
Pharmacokinetic Excellence
Comprehensive pharmacokinetic data from 40 healthy male volunteers across five dosing levels (4.21-140.45 nmol/kg) reveal dose-proportional kinetics with a terminal half-life of 2 hours, clearance of 0.078 L/h/kg, and volume of distribution of 0.22 L/kg[20][21]. GH stimulation demonstrates a single episode of release with peak concentrations at 0.67 hours[20].
Clinical Applications
Phase 2 randomized controlled trials focused on gastrointestinal applications, with 117 patients undergoing bowel resection surgery receiving ipamorelin (0.03 mg/kg twice daily) versus placebo for up to 7 days[22]. While primary efficacy endpoints showed modest results, ipamorelin demonstrated excellent tolerability with fewer adverse events than placebo (87.5% vs 94.8%)[22].
Ibutamoren (MK-677): The Oral Alternative
Pharmacological Profile
Ibutamoren offers unique advantages as an orally active, selective agonist of the ghrelin receptor with a 24-hour half-life[1]. This long duration allows once-daily dosing at 25 mg, providing sustained GH stimulation without injection requirements[1].
Clinical Evidence and Limitations
A comprehensive 12-month study in 65 healthy adults aged 60-81 years demonstrated sustained increases in pulsatile GH secretion and fat-free mass[23]. However, significant safety concerns emerged when a clinical trial examining MK-677 for hip fracture recovery in elderly patients was stopped early due to increased rates of congestive heart failure (6.5% vs 1.7% in placebo group)[18][24]. The FDA subsequently listed ibutamoren as posing "significant safety risks due to the potential for congestive heart failure in certain patients"[24].
Regulatory Status and Warnings
Despite its research potential, MK-677 remains unapproved for human consumption and appears on the DoD Prohibited Dietary Supplement Ingredients List and WADA Prohibited List[24]. Long-term safety concerns include potential increases in fasting blood glucose, hyperglycemia risk, and negative impacts on bone mineral density[24].
Hexarelin and CJC-1295: Extended Duration Compounds
Hexarelin Clinical Data
Hexarelin demonstrates substantial dose-dependent GH release in human subjects, with peak concentrations occurring at 30 minutes and returning to baseline within 240 minutes[25][26]. Clinical studies show ED50 values of 0.50-0.64 μg/kg, with effects after 2 μg/kg doses approaching maximal response[25]. However, chronic hexarelin therapy results in partial and reversible attenuation of GH response, with biological impact on the GH-IGF-1 axis being minimal during extended use[27].
CJC-1295: Long-Acting GHRH Analog
CJC-1295, a GHRH analog with albumin-binding properties, demonstrates remarkable pharmacokinetics with a half-life of 5.8-8.1 days[28][29]. Single injections produce dose-dependent increases in plasma GH concentrations by 2-10-fold for 6 days or more, with IGF-1 levels increasing 1.5-3-fold for 9-11 days[28]. Multiple doses maintain elevated IGF-1 levels for up to 28 days with preserved GH pulsatility[29][30].
Clinical Protocol Applications and Dosing Strategies
Weight Loss and Age Management Protocols
For weight loss and age management applications, sermorelin monotherapy typically employs 1,000 mcg subcutaneously at bedtime, increasing up to 2,000 mcg total daily based on IGF-1 responses[1]. Maintenance protocols often utilize 1,000 mcg three times weekly once therapeutic levels are achieved[1].
Combination Therapy Approaches
Sermorelin/ipamorelin combinations (500/500 mcg subcutaneously at bedtime) provide enhanced GH release compared to sermorelin alone while avoiding the hunger and hormonal side effects associated with GHRP-2 and GHRP-6[1]. This combination can be increased to 2,000 mcg total daily depending on IGF-1 laboratory results[1].
Weight Gain and Anabolic Protocols
For patients requiring weight gain and maximum GH response, GHRP-2/GHRP-6/sermorelin combinations (667/200/500 mcg subcutaneously before meals or twice/three times daily) provide the most significant hunger increase and anabolic stimulus[1].
Safety Considerations and Contraindications
Universal Contraindications
All growth hormone secretagogues share common contraindications including pregnancy, active malignancy, history of malignancy, diabetic proliferative retinopathy, sclerosing diseases of the liver and lungs, benign intracranial hypertension, and uncontrolled diabetes[1].
Timeline for Clinical Benefits
Patients typically require at least 3 months of consistent therapy before experiencing benefits, with full therapeutic effects usually apparent by 6 months[1]. This extended timeline necessitates patient education and realistic expectation setting for optimal treatment outcomes.
Regulatory Landscape and Legal Considerations
Current FDA Status
The regulatory environment for growth hormone secretagogues varies significantly by compound and application. While tesamorelin maintains FDA approval for specific indications, most other peptides exist in a complex regulatory framework involving compounding pharmacy regulations under Section 503A of the Federal Food, Drug & Cosmetic Act[31][32].
Compounding Restrictions and Biologics Classification
The 2020 implementation of the Biologics Price Competition and Innovation Act reclassified many peptides as biologics (compounds with >40 amino acids), removing them from compounding eligibility[31][32]. Peptides with ≤40 amino acids remain potentially eligible for compounding if they meet specific criteria: appearing in FDA-approved products, having USP monographs, or being listed on the Section 503A Bulks List[32][33].
Off-Label Prescribing Considerations
Unlike recombinant human growth hormone, which has legal restrictions on clinical use, the off-label prescribing of compounds like sermorelin is not prohibited by federal law[3][1]. This distinction provides clinicians with greater flexibility in therapeutic applications while maintaining appropriate medical supervision.
Recent FDA Actions
The FDA has increased scrutiny of peptide compounding, placing several growth hormone secretagogues on Category 2 of the bulk substances list, indicating "significant safety risks"[34][35]. These actions reflect ongoing efforts to balance patient access with safety considerations in an evolving regulatory environment.
Future Directions and Clinical Implications
The clinical evidence supporting growth hormone secretagogues demonstrates their potential as safer alternatives to direct GH replacement therapy. Their ability to work within physiological feedback mechanisms, combined with extensive safety data from clinical trials, positions these compounds as valuable therapeutic tools for addressing age-related GH decline and specific medical conditions.
However, the evolving regulatory landscape requires careful navigation by healthcare providers and patients. The distinction between FDA-approved applications (such as tesamorelin for HIV lipodystrophy) and off-label uses necessitates informed clinical decision-making based on risk-benefit analyses and patient-specific factors.
The future of growth hormone secretagogue therapy likely depends on continued clinical research, regulatory clarification, and the development of standardized treatment protocols that maximize therapeutic benefits while minimizing potential risks. As our understanding of these compounds deepens, they may play increasingly important roles in age management, metabolic optimization, and specific disease treatment protocols.
References:
Peptide Information and Descriptions - Excel Male TRT Forum
Sermorelin Therapy Benefits, Risks, Uses, Approval, and Side Effects
Sermorelin: A better approach to management of adult-onset growth hormone insufficiency? - PMC
FDA approves tesamorelin for reduction of central fat accumulation | HIV i-Base
FDA Approves F8 Formulation of Theratechnologies' Tesamorelin for HIV-Associated Lipodystrophy
https://www.theratech.com/news-rele...eceives-fda-approval-egrifta-wrtm-tesamorelin
https://www.drugs.com/history/egrifta-wr.html
https://onlinelibrary.wiley.com/doi/full/10.1002/jcsm.12028
https://www.nature.com/articles/pr1994725
https://archive.hshsl.umaryland.edu/bitstreams/b11e0b7d-27cf-4e26-813d-2035f73c54f4/download
https://pubmed.ncbi.nlm.nih.gov/23099431/
https://www.sciencedirect.com/science/article/abs/pii/S0739724000000503
https://www.sciencedirect.com/science/article/abs/pii/S0196978197000168
https://pmc.ncbi.nlm.nih.gov/articles/PMC2824650/
https://pubmed.ncbi.nlm.nih.gov/26401470/
https://pmc.ncbi.nlm.nih.gov/articles/PMC4575555/
https://pubmed.ncbi.nlm.nih.gov/9849822/
https://pmc.ncbi.nlm.nih.gov/articles/PMC5632578/
https://swolverine.com/blogs/blog/i...imal-protocols-for-recovery-and-muscle-growth
https://pubmed.ncbi.nlm.nih.gov/10496658/
https://link.springer.com/article/10.1023/A:1018955126402
https://pubmed.ncbi.nlm.nih.gov/25331030/
https://pmc.ncbi.nlm.nih.gov/articles/PMC2757071/
https://www.opss.org/article/performance-enhancing-substance-mk-677-ibutamoren
https://link.springer.com/article/10.1007/BF00191904
https://pubmed.ncbi.nlm.nih.gov/7957536/
https://academic.oup.com/jcem/article-abstract/83/5/1644/2865542
https://pubmed.ncbi.nlm.nih.gov/16352683/
https://academic.oup.com/jcem/article/91/3/799/2843281
https://academic.oup.com/jcem/article/91/12/4792/2656274
https://newdrugloft.com/compounding-peptides-what-prescribers-should-know/
https://join.a4pc.org/hubfs/PDFs/2022-08-Prescriber-Briefing-Peptides_4-Aug-2022.pdf
https://www.frierlevitt.com/articles/regulatory-status-of-peptide-compounding-in-2025/
https://www.fda.gov/drugs/human-dru...pounding-may-present-significant-safety-risks
https://honehealth.com/edge/fda-peptide-ban/
Here is some basic information regarding the different GH secretagogues
Hormones involved and related analog drugs
•Growth Hormone Releasing Hormone:
1. Sermorelin
2. Tesamorelin
•Ghrelin:
1. GHRP
2. Ipamorelin
3. Ibutamoren
•Somatostatin
•Growth Hormone
1. Recumbent human growth hormone (rHGH)
•Insulin-Like Growth Factor-1
1. recumbent IGF-1
Growth Hormone Releasing Hormone (GHRH)
•Produced by hypothalamus
•Stimulates GH synthesis and RELEASE
•Binds to the GHRH-R in pituitary
•Short half-life ~12 min
•Increases # of somatotropes AND amount of GH secreted from each
•No down regulation of GH
Ghrelin
•Bind to GHRP-R (“Ghrelin receptor”) in pituitary to release GH
•Reduce inhibition by Somatostatin at pituitary
•Distinct and separate path than GHRH
•Stimulate GHRH production from hypothalamus
•Inhibit Somatostatin production from hypothalamus
Somatostatin (SS)
•“SS” aka Growth Hormone Inhibiting Hormone (GHIH) or Somatotropin Release-Inhibiting Factor (SRIF)
•Produced primarily by hypothalamus
•Inhibits GH synthesis and release
•Makes hypothalamus resistant to stimulation by GHRH and hypoglycemia
•Responsible for pulsatile GH inhibition
•Decreases number of somatotropes, not amount of GH production by each
•Increases with age
Sermorelin
•Geref—Sermorelin Acetate for Injection
•Analog of GHRH - First 29 amino acids
•Used for traditional GH stimulation testing
•T ½ 12 mins. IV or SC
•Up regulates own receptor
•Promotes non-REM slow wave sleep
•Dose: 1,000-2,000mcg SQ qhs
Growth Hormone Releasing Peptides (GHRP)
•Synthetic forms of Ghrelin
•GHRP-1, GHRP-2, GHRP-6, MK-0677,
Hexarelin, Ipamorelin, Ghrelin
•Simple, short-chained amino acid complexes
•Bind to GHRP-R GH
•“Artificial amplification” b/c works with endogenous GHRH
Sermorelin / GHRP-2 / GHRP-6
•Increases prolactin and cortisol
•Significantly increases hunger and gastric emptying
•Cost effective
•GHRPs will start a pulse, and acts synergistically with GHRPs, so there is no need to be concerned about administration timing if you co-administer GHRPs with Sermorelin.
•GHRPs Requires Endogenous Hypothalamic GHRH for Maximal GH Stimulation
–NAUSHIRA PANDYA, ROBERTA DEMOTT-FRIBERG, CYRIL Y. BOWERS, ARIEL L. BARKAN, AND CRAIG A. JAFFE, Journal of Clinical Endocrinology and Metabolism 1998 Vol. 83, No
•Dose: Recon with 7.5mL Bac Water, Inject 0.25mL SQ bid/tid
Sermorelin / Ipamorelin
•For higher GH release than Sermorelin alone
•Ipamorelin like GHRP-2 and GHRP-6, but does not induce hunger, prolactin or cortisol release
•Dose: 500/500mcg SQ qhs. Increase to 1,000/1,000mcg depending on IGF-1 lab results.
Ibutamoren
•Selective agonist of the ghrelin receptor
•Long acting (T ½ 24h)
•Orally active
•Studied in treatment of obesity, bone density and muscle mass
•Dose: 25mg po qd
rHGH vs GHRH / GHRP
•GHRH / GHRP significantly less expensive than rHGH
•HGH overdosing is minimized or completely avoided with GHRH / GHRP
•Tissue exposure to HGH released by the pituitary under the influence of GHRH / GHRP is episodic not “square wave”, preventing tachphylaxis by mimicking normal physiology
•By stimulating the pituitary, GHRH / GHRP preserves more of the growth hormone neuroendocrine axis which fails first during aging
•GHRH / GHRP blocks the cascade of hypophyseal hormone failure that occurs during aging, thereby preserving youthful anatomy and physiology
•GHRH / GHRP provides all the benefits of HGH replacement therapy and more, YET IT’S OFF LABEL USE IS NOT PROHIBITED BY FEDERAL LAW
Commonly Prescribed Protocols I have observed
•Sermorelin
–Weight Loss / Age Management (Inject 1,000 mcg SQ qhs)
–Increase up to 2,000 mcg total daily
–IGF-1 Maintenance protocol 1,000mcg tiw
•GHRP-2/GHRP-6/Sermorelin
–Weight gain and high GH Response (Inject 667/200/500mcg SQ before meals or bid/tid)
–Most significant hunger increase
•Sermorelin/Ipamorelin
–Weight Loss / Age Management / Lean Mass (Inject 500/500 mcg SQ qhs)
–Increase up to 2,000 mcg total daily
–IGF-1 Maintenance protocol 1,000mcg tiw
•Ibutamoren
–Age Management / Fat Loss / Lean Mass Increase (25mg po qd)
–No need for injections
–Long T ½
–Some patients will exhibit hunger
•Patients will not start exhibiting the benefits of GHRT until at least 3 months of being on their program and it usually takes about 6 months to see the full benefits of the therapy.
Contraindications
•Pregnancy
•Malignancy
•History of Malignancy
•Diabetic proliferative retinopathy
•Sclerosing diseases of the liver and lungs
•Benign intracranial hypertension
•Uncontrolled diabetes
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