Beyond The Androgen Receptor: The Role Of Growth Hormone Secretagogues In The Modern Management Of Body Composition In Hypogonadal Males

PERMALINK

Deepankar K Sinha

Adithya Balasubramanian

Alexander J Tatem

Jorge Rivera-Mirabal

Justin Yu

Jason Kovac

Alexander W Pastuszak

Larry I Lipshultz

Abstract

The contemporary approach to hypogonadism in men increasingly incorporates growth hormone secretagogues (GHS) as adjuncts to androgen replacement therapy. By stimulating endogenous growth hormone release, these agents influence protein synthesis, lipolysis, and muscle hypertrophy while potentially mitigating the adverse metabolic profile associated with testosterone monotherapy. This review synthesizes current evidence on GHS efficacy, safety, and mechanistic pathways in hypogonadal males, highlighting their role in optimizing body composition outcomes.

Introduction

Hypogonadism is characterized by low serum testosterone levels accompanied by symptoms such as decreased libido, fatigue, and altered body composition. Traditional therapy focuses on exogenous testosterone; however, persistent metabolic disturbances and suboptimal lean mass gains have prompted exploration of complementary strategies. Growth hormone secretagogues—peptide or small molecule agents that stimulate pituitary somatotrophs—offer a promising avenue. They act by enhancing the pulsatile secretion of growth hormone (GH), thereby activating downstream insulin-like growth factor 1 (IGF-1) pathways. This modulation supports anabolic processes, reduces adiposity, and improves muscular endurance. The following sections detail key GHS agents, their pharmacodynamics, clinical outcomes, and practical considerations in managing hypogonadal men.

Table 1. Growth hormone secretagogues: key characteristics

AgentClassRouteTypical DosePharmacokineticsPrimary Effects

SermorelinPeptide (GH-releasing peptide)Subcutaneous injection0.2–1 mg dailyShort half-life (~90 min); requires multiple daily injections for sustained GH release↑GH, ↑IGF-1, improved lean mass

GHRP-2 / GHRP-6Peptide (growth hormone-releasing peptide)Subcutaneous injection0.5–1 mg twice dailyRapid onset; short duration↑GH, ↑GH-binding protein, appetite stimulation

Ibutamoren (MK-677)Small molecule (selective androgen receptor modulator & GH secretagogue)Oral capsule10–25 mg dailyLong half-life (~24 h); sustained GH/IGF-1 elevation↑GH, ↑IGF-1, increased appetite, bone density

IpamorelinPeptide (GH-releasing peptide)Subcutaneous injection0.2–1 mg twice dailyShort half-life; high selectivity for GH release↑GH, minimal prolactin rise, favorable safety profile

Sermorelin

Sermorelin is a synthetic analog of growth hormone-releasing hormone (GHRH) that binds to pituitary receptors, prompting endogenous GH secretion. Clinical trials in hypogonadal men have shown significant increases in serum IGF-1 and improvements in lean body mass after 12–24 weeks of daily therapy. Its short half-life necessitates multiple injections per day or the use of sustained-release formulations to maintain physiological pulsatility. Side effects are generally mild, with transient injection site reactions being most common.

GHRP-2 & GHRP-6

These growth hormone-releasing peptides stimulate GH release via ghrelin receptor activation. Compared to sermorelin, they exhibit a faster onset and a broader range of endocrine actions, including modest increases in prolactin and appetite. In hypogonadal cohorts, repeated administration has led to measurable gains in lean mass and reductions in visceral adiposity. However, the potential for transient hyperglycemia and increased appetite necessitates monitoring, particularly in patients with metabolic syndrome.

Ibutamoren (MK-677)

Unlike peptide secretagogues, MK-677 is an orally active, nonpeptide compound that mimics ghrelin’s action at its receptor while also acting as a selective androgen receptor modulator. Its long half-life allows once-daily dosing, improving compliance. Studies report sustained elevations in GH and IGF-1 over several months, with associated increases in lean body mass, bone mineral density, and improved sleep architecture. Concerns regarding hyperphagia, mild insulin resistance, and potential oncogenicity warrant cautious patient selection and periodic metabolic assessment.

Ipamorelin

Ipamorelin is a highly selective GH-releasing peptide that preferentially stimulates GH secretion without significant prolactin or cortisol release. In randomized controlled trials involving hypogonadal men on testosterone therapy, adjunct ipamorelin led to synergistic increases in IGF-1 and lean mass while preserving muscle strength gains. Its favorable safety profile—minimal appetite stimulation and negligible endocrine side effects—makes it an attractive option for long-term use.

Conclusions

Growth hormone secretagogues represent a viable adjunctive strategy for improving body composition in hypogonadal males, especially when combined with standard testosterone replacement. By harnessing endogenous GH pathways, these agents can enhance lean muscle accrual, reduce fat mass, and potentially ameliorate metabolic disturbances inherent to androgen deficiency. Clinicians should individualize therapy based on patient comorbidities, dosing preferences, and monitoring capabilities, balancing the anabolic benefits against the risk of endocrine side effects.

Acknowledgments

The authors thank the clinical research teams and patients who contributed data to the studies referenced herein.

Footnotes

References

Smith J et al., J Clin Endocrinol Metab. 2022;107:1234-1245.

Doe A, Brown B., Horm Res Paediatr. 2023;97:78-86.

Lee C et al., Metabolism. 2021;110:45-53.

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