A Deep Dive into Growth Hormone Secretagogues (Peptides): Clinical Evidence, Mechanisms, and Therapeutic Applications

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:

1. Peptide Information and Descriptions - Excel Male TRT Forum
2. Sermorelin Therapy Benefits, Risks, Uses, Approval, and Side Effects
3. Sermorelin: A better approach to management of adult-onset growth hormone insufficiency? - PMC
4. FDA approves tesamorelin for reduction of central fat accumulation | HIV i-Base
5. FDA Approves F8 Formulation of Theratechnologies' Tesamorelin for HIV-Associated Lipodystrophy
6. https://www.theratech.com/news-rele...eceives-fda-approval-egrifta-wrtm-tesamorelin
7. https://www.drugs.com/history/egrifta-wr.html
8. https://onlinelibrary.wiley.com/doi/full/10.1002/jcsm.12028
9. https://www.nature.com/articles/pr1994725
10. https://archive.hshsl.umaryland.edu/bitstreams/b11e0b7d-27cf-4e26-813d-2035f73c54f4/download
11. https://pubmed.ncbi.nlm.nih.gov/23099431/
12. https://www.sciencedirect.com/science/article/abs/pii/S0739724000000503
13. https://www.sciencedirect.com/science/article/abs/pii/S0196978197000168
14. https://pmc.ncbi.nlm.nih.gov/articles/PMC2824650/
15. https://pubmed.ncbi.nlm.nih.gov/26401470/
16. https://pmc.ncbi.nlm.nih.gov/articles/PMC4575555/
17. https://pubmed.ncbi.nlm.nih.gov/9849822/
18. https://pmc.ncbi.nlm.nih.gov/articles/PMC5632578/
19. https://swolverine.com/blogs/blog/i...imal-protocols-for-recovery-and-muscle-growth
20. https://pubmed.ncbi.nlm.nih.gov/10496658/
21. https://link.springer.com/article/10.1023/A:1018955126402
22. https://pubmed.ncbi.nlm.nih.gov/25331030/
23. https://pmc.ncbi.nlm.nih.gov/articles/PMC2757071/
24. https://www.opss.org/article/performance-enhancing-substance-mk-677-ibutamoren
25. https://link.springer.com/article/10.1007/BF00191904
26. https://pubmed.ncbi.nlm.nih.gov/7957536/
27. https://academic.oup.com/jcem/article-abstract/83/5/1644/2865542
28. https://pubmed.ncbi.nlm.nih.gov/16352683/
29. https://academic.oup.com/jcem/article/91/3/799/2843281
30. https://academic.oup.com/jcem/article/91/12/4792/2656274
31. https://newdrugloft.com/compounding-peptides-what-prescribers-should-know/
32. https://join.a4pc.org/hubfs/PDFs/2022-08-Prescriber-Briefing-Peptides_4-Aug-2022.pdf
33. https://www.frierlevitt.com/articles/regulatory-status-of-peptide-compounding-in-2025/
34. https://www.fda.gov/drugs/human-dru...pounding-may-present-significant-safety-risks
35. 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

 

@pscarb created this guide:

The Very Basic Guide to GHRP/GHRH Peptides - Team Pscarb Coaching

The new muscle building/fat loss supplement to be used by Bodybuilders these days are Peptides, these naturally pulse HGH in the body, the problem is though is that many articles make it all to confusing, much more than it needs to be so i thought it would be a good article to write to try […]

teampscarb.co.uk

 

peptides excelmale.com site:www.excelmale.com - Google Search

 

Click on this image to download my slide presentation:



This document, "GH Secretagogue Webinar.pdf," discusses Growth Hormone (GH) and Growth Hormone Secretagogues (GHS).

Here's a summary of its key points:

• GH Production and Regulation: GH release is stimulated by Growth Hormone Releasing Hormone (GHRH) from the hypothalamus and Ghrelin from the stomach. It exerts effects directly and via IGF-1 production. GH secretion is pulsatile, largely occurring during sleep. Factors like decreased blood glucose, fasting, exercise, testosterone, and deep sleep stimulate GH, while increased blood glucose, aging, obesity, and somatostatin inhibit it (Pages 2-5).
• FDA Approved GH Brands and Indications: The document lists several FDA-approved GH brands (e.g., Genotropin, Humatrope) and their indications, which include pediatric and adult GHD, Turner syndrome, chronic renal insufficiency, idiopathic short stature, Prader-Willi Syndrome, and HIV wasting or cachexia (Page 6).
• GH Contraindications and Side Effects: Contraindications for GH include pregnancy, malignancy, uncontrolled diabetes, and benign intracranial hypertension. Side effects can include edema, hyperglycemia, carpal tunnel syndrome, joint and muscle pain, and abnormal skin sensations. Exogenous GH can also suppress endogenous GH and GHRH production (Pages 7, 10).
• GH Legality and Deficiency Testing: Human growth hormone is not a controlled substance but its distribution for non-medical use is criminalized. Prescribing GH for adult GHD requires strict stimulation tests, which are labor-intensive and involve multiple blood samples. GH secretagogues are not controlled and can be used without these requirements (Pages 11-12).
• Available Products Involved in GH Release: These include Growth Hormone Releasing Hormones (Sermorelin, Tesamorelin), Ghrelin Agonists (GHRP-2, GHRP-6, Ipamorelin, Ibutamoren), Somatostatin, and Synthetic Human Growth Hormone (rHGH) (Page 13).
• GHS vs. rHGH: GHRH/GHS are significantly less expensive than rHGH, minimize or avoid overdosing, and provide physiologic, episodic GH release, mimicking normal physiology. They also help preserve the growth hormone neuroendocrine axis that fails with aging (Page 16).
• Specific GHS Products and Protocols:
  • Sermorelin Acetate: A GHRH analog, typically prescribed for younger patients with healthy pituitary function. It improves sleep, promotes hGH and IGF-1 synthesis, and can reduce body fat. It's administered subcutaneously in 12-week cycles followed by a 30-day holiday or alternative medication (Pages 24-25).
  • Ipamorelin Acetate: A ghrelin agonist that stimulates GH release and inhibits somatostatin. It appears more effective than Sermorelin at increasing IGF-1, does not increase hunger, and has a reduced risk of increasing cortisol and prolactin. It's often used in aging patients and for body composition changes, typically taken chronically (Pages 26-28).
  • Ibutamoren (MK-677): An orally active ghrelin receptor agonist and potent GH secretagogue. It's used for significant increases in lean body mass, bone density, and fat loss, offering 24 hours of activity. Side effects can include transient appetite increase, edema, and muscle pain (Pages 35-37).
  • Combination Therapies: Combining Sermorelin with GHRPs (like GHRP-2 or Ipamorelin) can have a synergistic effect, resulting in a more robust GH release. This is often recommended for severe GHD or older patients (Pages 29-34, 38-40).
• Commercial GHS Products: EGRIFTA® (Tesamorelin acetate) is the only commercially available GHRH product in the US, indicated for abdominal fat reduction in HIV-infected patients. Geref® (sermorelin acetate) was discontinued but its active ingredient is available through compounding pharmacies (Pages 42-43).

 

What are Growth Hormone Secretagogues (GHS) and how do they differ from direct Growth Hormone (GH) replacement therapy?​

• Growth Hormone Secretagogues (GHS) are compounds, often peptides, that stimulate the body's natural production and release of Growth Hormone (GH). They achieve this by acting on specific pathways in the brain and pituitary gland, primarily by mimicking Growth Hormone Releasing Hormone (GHRH) or ghrelin, and by inhibiting somatostatin (a GH-inhibiting hormone).
• The key difference between GHS and direct GH replacement (rHGH) lies in their mechanism and physiological impact. GHS work by encouraging the body to produce its own GH, leading to episodic, natural pulses of GH release, similar to how the body functions normally. This "episodic" exposure helps prevent tachyphylaxis (reduced response over time) and preserves the natural neuroendocrine axis of GH production. In contrast, direct rHGH replacement provides a constant, exogenous supply of GH, which can suppress the body's natural GH and GHRH production and may lead to different side effect profiles. Additionally, GHS are generally less expensive than rHGH and their off-label use is not prohibited by federal law, unlike rHGH which has stricter legal restrictions on its clinical use.

How do Growth Hormone Releasing Hormone (GHRH) analogs like Sermorelin and Tesamorelin work, and what are their primary applications?​

• GHRH analogs, such as Sermorelin and Tesamorelin, mimic the action of naturally occurring Growth Hormone Releasing Hormone (GHRH), which is produced by the hypothalamus. They bind to GHRH receptors in the pituitary gland, stimulating both the synthesis and release of GH. This action also increases the number of somatotropes (GH-producing cells) and the amount of GH secreted from each cell, without causing downregulation.
• Sermorelin, an analog containing the first 29 amino acids of natural GHRH, has a short half-life (around 12 minutes) and is typically administered subcutaneously at bedtime to align with the body's natural GH pulse. It is used to increase hGH levels, improve general well-being, enhance lean body mass, improve insulin sensitivity, and support libido, particularly in age management protocols. It also upregulates its own receptor and promotes non-REM slow-wave sleep.
• Tesamorelin is a more clinically validated GHRH analog, holding FDA approval since 2010 for reducing excess abdominal fat in HIV-infected patients with lipodystrophy. Clinical trials showed significant reductions in abdominal fat. Its approval makes it a standout for its demonstrated efficacy and established safety profile in a specific medical indication. A newer formulation, EGRIFTA WR, offers weekly reconstitution for convenience.

What are Ghrelin Mimetics (GHRPs) and how do they function, distinguishing between GHRP-6, GHRP-2, and Ipamorelin?​

• Ghrelin Mimetics, also known as Growth Hormone Releasing Peptides (GHRPs), are synthetic forms of ghrelin. They bind to GHRP receptors (ghrelin receptors) in the pituitary gland to stimulate GH release. Their unique mechanism also involves reducing somatostatin inhibition and stimulating GHRH production from the hypothalamus, creating an "artificial amplification" that synergizes with endogenous GHRH.
• GHRP-6: A potent stimulator of GH secretion, GHRP-6 has a relatively short half-life and shows dose-dependent GH increases. A notable side effect is a significant increase in hunger and gastric emptying, making it useful for weight gain protocols. It also increases prolactin and cortisol levels.
• GHRP-2: Demonstrated to be 2-3 times more effective at stimulating GH release than GHRP-6. Like GHRP-6, it significantly increases hunger and gastric emptying, and can also increase prolactin and cortisol levels. It has been clinically shown to increase food intake and was successfully used in a severely emaciated anorexia nervosa patient to promote weight gain and improve strength.
• Ipamorelin: Stands out as the most selective GHS. Its unique advantage is its ability to stimulate GH release without significantly affecting cortisol, ACTH, or prolactin levels, even at high doses. This selectivity leads to a superior tolerability profile with minimal appetite stimulation, slight water retention, or temporary flushing. Its pharmacokinetic profile shows a terminal half-life of 2 hours, making it a preferred choice for those seeking GH benefits without the hunger or hormonal side effects associated with other GHRPs.

What is Ibutamoren (MK-677), and what are its clinical uses, advantages, and safety concerns?​

• Ibutamoren (MK-677) is an orally active, selective agonist of the ghrelin receptor, offering a unique advantage due to its oral administration and long half-life of 24 hours. This allows for convenient once-daily dosing, providing sustained GH stimulation without the need for injections.
• Clinically, ibutamoren has been studied for its potential in increasing lean body mass, improving bone density, and aiding fat loss. A 12-month study in healthy older adults showed sustained increases in pulsatile GH secretion and fat-free mass.
• However, significant safety concerns have emerged. A clinical trial investigating MK-677 for hip fracture recovery in elderly patients was stopped early due to an increased rate of congestive heart failure. Consequently, the FDA has listed ibutamoren as posing "significant safety risks" and it remains unapproved for human consumption. It is also on the DoD Prohibited Dietary Supplement Ingredients List and WADA Prohibited List. Long-term safety concerns include potential increases in fasting blood glucose, hyperglycemia risk, and negative impacts on bone mineral density.

What are the common dosing strategies and combination therapies involving GHS, and how long does it take to see benefits?​

• Dosing strategies for GHS vary depending on the desired outcome, typically administered subcutaneously at bedtime to align with the body's natural GH release.
• Weight Loss and Age Management: Sermorelin monotherapy often starts at 1,000 mcg subcutaneously at bedtime, potentially increasing up to 2,000 mcg daily based on IGF-1 responses. Maintenance protocols might involve 1,000 mcg three times weekly.
• Enhanced GH Release/Lean Mass (without hunger): A common combination is Sermorelin/Ipamorelin (e.g., 500/500 mcg subcutaneously at bedtime). This combination can be increased up to 2,000 mcg total daily, aiming for higher GH release than Sermorelin alone, while avoiding the hunger and hormonal side effects of GHRP-2 and GHRP-6.
• Weight Gain and Anabolic Protocols (with hunger): For patients needing maximum GH response and significant hunger increase, combinations like GHRP-2/GHRP-6/Sermorelin (e.g., 667/200/500 mcg subcutaneously before meals or twice/thrice daily) are utilized.
• Oral Convenience: Ibutamoren (MK-677) offers an oral alternative at 25 mg daily for age management, fat loss, and lean mass increase, beneficial for those who prefer no injections. However, its significant safety concerns should be noted.
• Patients typically need at least 3 months of consistent therapy to start experiencing benefits, with full therapeutic effects usually becoming apparent by 6 months. This requires patient education and realistic expectation setting for optimal treatment outcomes.

What are the contraindications and potential side effects associated with GHS therapy?​

• There are universal contraindications for all Growth Hormone Secretagogues to ensure patient safety:
• Pregnancy
• Active malignancy or history of malignancy
• Diabetic proliferative retinopathy
• Sclerosing diseases of the liver and lungs
• Benign intracranial hypertension
• Uncontrolled diabetes
• Potential side effects vary among different GHS compounds:
• Sermorelin: Generally well-tolerated with few serious adverse events. Mild, transient symptoms may include slight water retention or temporary flushing.
• Tesamorelin: Common adverse reactions include arthralgia, injection site reactions, pain in extremity, peripheral edema, and myalgia. Potential effects on blood sugar control require attention.
• GHRP-6 and GHRP-2: Significantly increase hunger and gastric emptying, which can be problematic for weight loss applications. They also increase prolactin and cortisol levels.
• Ipamorelin: Distinguished by its selective profile, it causes only mild, transient symptoms such as slight water retention, temporary flushing, and minimal appetite stimulation, without significantly affecting cortisol or prolactin.
• Ibutamoren (MK-677): While offering a long half-life and oral administration, it carries significant safety concerns, including an increased risk of congestive heart failure in certain elderly patients. Other concerns include potential increases in fasting blood glucose, hyperglycemia risk, and negative impacts on bone mineral density.

What is the current regulatory landscape for GHS in the US, particularly regarding FDA approval and compounding?​

• The regulatory landscape for Growth Hormone Secretagogues in the US is complex and evolving.
• FDA Approval:
• Tesamorelin (EGRIFTA®/EGRIFTA WR™) is the only GHS with full FDA approval for a specific indication: reducing excess abdominal fat in HIV-infected patients with lipodystrophy. This makes it a clinically validated and commercially available product for its approved use.
• Other GHS compounds, like Sermorelin, are not FDA-approved as standalone drugs for general use. Geref® (sermorelin acetate) was discontinued commercially but its active ingredient remains available through compounding pharmacies.
• Compounding Pharmacy Regulations:
• Most other peptides fall under Section 503A of the Federal Food, Drug & Cosmetic Act for compounding pharmacies.
• A significant change occurred with the 2020 implementation of the Biologics Price Competition and Innovation Act, which reclassified many peptides as "biologics" (compounds with >40 amino acids), removing them from compounding eligibility.
• Peptides with ≤40 amino acids may still be eligible for compounding if they meet specific criteria: being in FDA-approved products, having USP monographs, or being listed on the Section 503A Bulks List.
• The FDA has increased scrutiny on peptide compounding, placing several GHS on "Category 2" of the bulk substances list, indicating "significant safety risks," reflecting ongoing efforts to balance patient access with safety.
• Off-Label Prescribing:
• Unlike recombinant human growth hormone (rHGH), which has strict legal restrictions on its clinical use, the off-label prescribing of compounded GHS like sermorelin is generally not prohibited by federal law. This distinction provides clinicians with more flexibility for therapeutic applications under appropriate medical supervision, while still navigating the evolving regulatory environment and potential safety concerns highlighted by the FDA.

What are the key advantages of GHS over direct rHGH replacement, and what does the future hold for GHS therapy?​

• Growth Hormone Secretagogues (GHS) offer several compelling advantages over direct recombinant human growth hormone (rHGH) replacement:

1. Physiological Release: GHS work by stimulating the body's own pituitary gland to release GH. This results in episodic, pulsatile GH secretion, which mimics the body's natural physiological pattern. In contrast, rHGH replacement provides a constant, "square wave" exposure, which can lead to tachyphylaxis (reduced response over time).
2. Preservation of Neuroendocrine Axis: By stimulating the pituitary, GHS help preserve the natural growth hormone neuroendocrine axis, which tends to decline with age. This can block the cascade of hypophyseal hormone failure.
3. Minimized Overdosing: The body's natural feedback mechanisms regulate GH release when GHS are used, minimizing the risk of overdosing on GH, which is a concern with direct rHGH.
4. Cost-Effectiveness: GHS are significantly less expensive than rHGH, making them a more accessible option for many patients.
5. Regulatory Flexibility (Off-Label): While FDA approval varies, the off-label prescribing of compounded GHS like sermorelin is not federally prohibited, unlike rHGH, offering clinicians greater flexibility.
6. Safety Profile: Overall, GHS are generally considered safer alternatives to direct GH replacement, with extensive safety data from clinical trials.

• The future of GHS therapy depends on continued clinical research, further regulatory clarification, and the development of standardized treatment protocols. As our understanding of these compounds deepens, they are poised to play increasingly important roles in age management, metabolic optimization, and the treatment of specific medical conditions, offering a physiologically sound approach to addressing growth hormone-related concerns.