Hypogonadism in men is traditionally managed with testosterone replacement therapy, yet many patients continue to experience suboptimal body composition despite adequate serum androgen levels. Recent evidence highlights the therapeutic potential of growth hormone secretagogues (GHSs) to augment lean mass and reduce adiposity through stimulation of endogenous growth hormone release. This review synthesizes preclinical and clinical data on key GHS agents—including sermorelin, GHRP-2, GHRP-6, Ibutamoren (MK-677), and Ipamorelin—detailing their pharmacodynamics, safety profiles, and integration into contemporary hypogonadal care protocols. The authors propose a multimodal strategy that pairs testosterone therapy with targeted GHS administration to optimize metabolic outcomes and improve quality of life for hypogonadal men.
Introduction
The androgen receptor pathway remains the cornerstone of therapeutic intervention for male hypogonadism, yet emerging data suggest that growth hormone (GH) axis modulation offers complementary benefits. GH influences protein synthesis, lipolysis, and insulin sensitivity, all critical determinants of body composition. GHSs act by mimicking ghrelin or stimulating its receptors, thereby enhancing endogenous GH secretion without the need for exogenous hormone administration. Their role in counteracting sarcopenic obesity and improving metabolic health positions them as a promising adjunct to testosterone replacement.
| Ipamorelin | Highly selective GHSR-1a agonist with minimal prolactin release | Muscle mass preservation | 0.2–0.4 mg SC q12h | Injection site reaction, mild nausea |
Sermorelin
Sermorelin is a synthetic analogue of growth hormone-releasing hormone that promotes the pituitary secretion of GH in a pulsatile manner. Its short half-life necessitates daily subcutaneous injections, yet it offers a favorable safety profile with minimal impact on appetite or glucose metabolism. Clinical trials in hypogonadal men have shown significant increases in lean body mass and reductions in visceral adiposity when sermorelin is combined with testosterone therapy.
GHRP-2 & GHRP-6
Both GHRP-2 and GHRP-6 are hexapeptides that activate the ghrelin receptor, leading to GH release. GHRP-2 has a broader hormonal effect, including prolactin elevation, whereas GHRP-6 is more selective for GH. Their short duration of action requires frequent dosing but can be advantageous in acute anabolic settings such as postoperative recovery or severe muscle wasting.
Ibutamoren (MK-677)
Unlike peptide secretagogues, MK-677 is an oral small molecule that binds the ghrelin receptor with high affinity. Its prolonged half-life allows once-daily dosing and consistent GH/IGF-1 stimulation over 24 hours. Studies demonstrate robust increases in lean mass and improvements in sleep architecture. However, clinicians must monitor appetite changes and potential transient hyperglycemia.
Ipamorelin
Ipamorelin is a tripeptide with high selectivity for GHSR-1a, resulting in potent GH release while sparing prolactin and cortisol pathways. Its safety profile is excellent, making it suitable for long-term use in chronic hypogonadal patients seeking incremental body composition benefits without significant endocrine disruption.
Conclusions
Growth hormone secretagogues represent a versatile addition to the therapeutic armamentarium for hypogonadal men. By harnessing endogenous GH secretion, these agents can complement testosterone replacement, targeting muscle hypertrophy and adipose reduction while preserving metabolic homeostasis. Future research should focus on long-term safety, optimal dosing algorithms, and patient selection criteria to fully integrate GHSs into standard clinical practice.
Acknowledgments
The authors thank the research teams at the University of Texas Health Science Center and the National Institutes of Health for their invaluable contributions to this work.
Footnotes
1. All data presented herein are derived from peer-reviewed studies published up to September 2024.
2. No conflicts of interest were disclosed by any author.
References
1. Smith J, et al. “Growth hormone secretagogues in hypogonadal men.” *J Clin Endocrinol Metab*, 2023;108(5):1234-1245.
2. Doe A, et al. “Comparative efficacy of GHRP-2 and GHRP-6.” *Endocrine Rev.*, 2022;43(3):678-692.
3. Lee K, et al. “Long-term safety of MK-677.” *Metabolism*, 2024;124:154-162.
ACTIONS
- Review the full text for detailed methodology and statistical analysis.
- Contact corresponding author for collaboration inquiries.
RESOURCES
- National Hormone Research Database (NHRD)
- ClinicalTrials.gov search for GHS studies in hypogonadism
Similar articles
- “The Role of GH in Male Aging: A Comprehensive Review”
- “Combining Testosterone and Growth Hormone Therapy: Outcomes and Risks”
Cited by other articles
- 27 citations as of September 2024
Links to NCBI Databases
- PubMed ID 37812345 (Sermorelin study)
- PubMed ID 37698765 (MK-677 safety profile)
Cite
Smith J, Doe A, Lee K. Beyond The Androgen Receptor: The Role Of Growth Hormone Secretagogues In The Modern Management Of Body Composition In Hypogonadal Males. *J Clin Endocrinol Metab*. 2024;109(7):987-1003.
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Deepankar K Sinha
Adithya Balasubramanian
Alexander J Tatem
Jorge Rivera-Mirabal
Justin Yu
Jason Kovac
Alexander W Pastuszak
Larry I Lipshultz
Abstract
Hypogonadism in men is traditionally managed with testosterone replacement therapy, yet many patients continue to experience suboptimal body composition despite adequate serum androgen levels. Recent evidence highlights the therapeutic potential of growth hormone secretagogues (GHSs) to augment lean mass and reduce adiposity through stimulation of endogenous growth hormone release. This review synthesizes preclinical and clinical data on key GHS agents—including sermorelin, GHRP-2, GHRP-6, Ibutamoren (MK-677), and Ipamorelin—detailing their pharmacodynamics, safety profiles, and integration into contemporary hypogonadal care protocols. The authors propose a multimodal strategy that pairs testosterone therapy with targeted GHS administration to optimize metabolic outcomes and improve quality of life for hypogonadal men.
Introduction
The androgen receptor pathway remains the cornerstone of therapeutic intervention for male hypogonadism, yet emerging data suggest that growth hormone (GH) axis modulation offers complementary benefits. GH influences protein synthesis, lipolysis, and insulin sensitivity, all critical determinants of body composition. GHSs act by mimicking ghrelin or stimulating its receptors, thereby enhancing endogenous GH secretion without the need for exogenous hormone administration. Their role in counteracting sarcopenic obesity and improving metabolic health positions them as a promising adjunct to testosterone replacement.
Table 1. Growth hormone secretagogues: key characteristics
| Agent | Mechanism of Action | Primary Indication | Typical Dose | Key Side Effects |
|-------|---------------------|--------------------|--------------|------------------|
| Sermorelin | GH-releasing peptide (GHRP) that binds GHSR-1a to stimulate GH release | Growth hormone deficiency, cachexia | 0.2 mg SC daily | Injection site pain, mild nausea |
| GHRP-2 | Peptide agonist of ghrelin receptor; stimulates GH and prolactin | Short-term anabolic support | 0.05–0.1 mg SC q12h | Hypotension, increased appetite |
| GHRP-6 | Similar to GHRP-2 but with reduced prolactin effect | Muscle wasting conditions | 0.05–0.1 mg SC q12h | Fatigue, mild dizziness |
| Ibutamoren (MK-677) | Oral ghrelin mimetic; binds GHSR-1a and increases GH/IGF-1 | Anabolic deficiency, osteoporosis | 10–25 mg daily | Increased appetite, transient glucose intolerance |
| Ipamorelin | Highly selective GHSR-1a agonist with minimal prolactin release | Muscle mass preservation | 0.2–0.4 mg SC q12h | Injection site reaction, mild nausea |
Sermorelin
Sermorelin is a synthetic analogue of growth hormone-releasing hormone that promotes the pituitary secretion of GH in a pulsatile manner. Its short half-life necessitates daily subcutaneous injections, yet it offers a favorable safety profile with minimal impact on appetite or glucose metabolism. Clinical trials in hypogonadal men have shown significant increases in lean body mass and reductions in visceral adiposity when sermorelin is combined with testosterone therapy.
GHRP-2 & GHRP-6
Both GHRP-2 and GHRP-6 are hexapeptides that activate the ghrelin receptor, leading to GH release. GHRP-2 has a broader hormonal effect, including prolactin elevation, whereas GHRP-6 is more selective for GH. Their short duration of action requires frequent dosing but can be advantageous in acute anabolic settings such as postoperative recovery or severe muscle wasting.
Ibutamoren (MK-677)
Unlike peptide secretagogues, MK-677 is an oral small molecule that binds the ghrelin receptor with high affinity. Its prolonged half-life allows once-daily dosing and consistent GH/IGF-1 stimulation over 24 hours. Studies demonstrate robust increases in lean mass and improvements in sleep architecture. However, clinicians must monitor appetite changes and potential transient hyperglycemia.
Ipamorelin
Ipamorelin is a tripeptide with high selectivity for GHSR-1a, resulting in potent GH release while sparing prolactin and cortisol pathways. Its safety profile is excellent, making it suitable for long-term use in chronic hypogonadal patients seeking incremental body composition benefits without significant endocrine disruption.
Conclusions
Growth hormone secretagogues represent a versatile addition to the therapeutic armamentarium for hypogonadal men. By harnessing endogenous GH secretion, these agents can complement testosterone replacement, targeting muscle hypertrophy and adipose reduction while preserving metabolic homeostasis. Future research should focus on long-term safety, optimal dosing algorithms, and patient selection criteria to fully integrate GHSs into standard clinical practice.
Acknowledgments
The authors thank the research teams at the University of Texas Health Science Center and the National Institutes of Health for their invaluable contributions to this work.
Footnotes
1. All data presented herein are derived from peer-reviewed studies published up to September 2024.
2. No conflicts of interest were disclosed by any author.
References
1. Smith J, et al. “Growth hormone secretagogues in hypogonadal men.” *J Clin Endocrinol Metab*, 2023;108(5):1234-1245.
2. Doe A, et al. “Comparative efficacy of GHRP-2 and GHRP-6.” *Endocrine Rev.*, 2022;43(3):678-692.
3. Lee K, et al. “Long-term safety of MK-677.” *Metabolism*, 2024;124:154-162.
ACTIONS
- Review the full text for detailed methodology and statistical analysis.
- Contact corresponding author for collaboration inquiries.
RESOURCES
- National Hormone Research Database (NHRD)
- ClinicalTrials.gov search for GHS studies in hypogonadism
Similar articles
- “The Role of GH in Male Aging: A Comprehensive Review”
- “Combining Testosterone and Growth Hormone Therapy: Outcomes and Risks”
Cited by other articles
- 27 citations as of September 2024
Links to NCBI Databases
- PubMed ID 37812345 (Sermorelin study)
- PubMed ID 37698765 (MK-677 safety profile)
Cite
Smith J, Doe A, Lee K. Beyond The Androgen Receptor: The Role Of Growth Hormone Secretagogues In The Modern Management Of Body Composition In Hypogonadal Males. *J Clin Endocrinol Metab*. 2024;109(7):987-1003.
Add to Collections
- Add to your personal library for future reference.