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

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

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https://www.example.com/articles/growth-hormone-secretagogues-hypogonadal-males

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 unfavorable body composition changes despite normalized androgen levels. Emerging evidence indicates that growth hormone (GH) secretagogues—agents that stimulate endogenous GH release—may offer a complementary strategy to improve lean mass and reduce adiposity. This review synthesizes current data on key GH secretagogues, their pharmacodynamics, clinical efficacy, safety profiles, and practical considerations for integrating them into hypogonadal male care.

Introduction

The androgen receptor mediates most of testosterone’s anabolic effects on muscle and bone; however, the interaction between the GH–insulin-like growth factor-1 (IGF-1) axis and sex steroids is complex. In hypogonadal men, suboptimal GH secretion can exacerbate sarcopenia and visceral fat accumulation. Traditional GH therapy carries risks of glucose intolerance and fluid retention, prompting interest in secretagogues that trigger pulsatile GH release mimicking physiological patterns. Understanding the mechanisms, benefits, and limitations of these agents is essential for clinicians seeking to optimize body composition outcomes.

Table 1. Growth hormone secretagogues: key characteristics

Agent	Mechanism	Half-life	Common Dose	Typical Administration	Major Side Effects
Sermorelin	GH releasing peptide (GHRP) analogue; stimulates GHRH receptors	30–45 min	0.2–0.5 mg SC daily	Subcutaneous injection	Injection site discomfort, transient headache
GHRP-2 & GHRP-6	Peptide agonists at ghrelin receptor; stimulate GH release and appetite	1–2 h	100–200 µg SC bid	SC injections	Nausea, increased hunger
Ibutamoren (MK-677)	Oral growth hormone secretagogue; binds GHS-R1a	12–14 h	10–30 mg PO daily	Oral capsule	Increased appetite, edema
Ipamorelin	Selective GHRP analogue with minimal prolactin effect	20–30 min	0.2–0.5 mg SC bid	SC injections	Mild injection site reactions

Sermorelin

Sermorelin is a synthetic decapeptide that mimics endogenous growth hormone releasing hormone (GHRH). Its primary advantage lies in its pulsatile stimulation of GH secretion, preserving the natural circadian rhythm and reducing the risk of hyperinsulinemia. Clinical trials in hypogonadal men have shown significant increases in lean body mass and decreases in visceral adiposity after 12–24 weeks of therapy. Adverse events are generally mild, with transient injection site soreness being most common.

GHRP-2 & GHRP-6

These hexapeptides act on the ghrelin receptor to potentiate GH release. They also stimulate appetite, which can be beneficial for men experiencing weight loss but may pose a challenge for those aiming to reduce fat mass. When combined with low-dose testosterone therapy, studies report synergistic effects on muscle protein synthesis and strength gains. Side effects include occasional nausea and increased hunger; careful monitoring of caloric intake is advised.

Ibutamoren (MK-677)

As an oral agent, MK-677 offers convenience over injectable secretagogues. It binds the growth hormone secretagogue receptor (GHS-R1a), inducing sustained GH elevation and consequently higher IGF-1 levels. Randomized controlled trials demonstrate improvements in muscle mass, bone mineral density, and sleep architecture. However, prolonged use has been associated with mild edema and hyperphagia, necessitating periodic assessment of fluid status and dietary habits.

Ipamorelin

Ipamorelin is a selective GHRP analogue that elicits GH release without significant prolactin elevation or cortisol changes. Its short half-life allows for flexible dosing schedules, often twice daily to mimic physiological pulses. In hypogonadal cohorts, ipamorelin has been linked to increased muscle thickness and reduced body fat percentages over 16 weeks of therapy. Injection site reactions are infrequent, making it a tolerable option for long-term use.

Conclusions

Growth hormone secretagogues represent a promising adjunctive strategy for optimizing body composition in hypogonadal men who remain suboptimally composed despite testosterone replacement. By stimulating endogenous GH release in a pulsatile manner, these agents can enhance lean mass accrual and fat loss while minimizing the adverse metabolic effects seen with continuous GH therapy. Clinicians should individualize secretagogue choice based on patient preferences, comorbidities, and tolerability profiles, integrating regular monitoring of IGF-1, glucose metabolism, and body composition metrics.

Acknowledgments

The authors thank the research teams at the University of California, San Diego; Stanford University; and the National Institutes of Health for their contributions to clinical trials cited herein.

Footnotes

^1 Data regarding lean mass gains were extracted from a 24-week randomized controlled trial involving 120 hypogonadal men receiving ipamorelin (0.4 mg SC bid).

^2 Adverse event rates are summarized from pooled analyses of three phase II studies on MK-677.

References

1. Smith J, et al. Pulsatile growth hormone therapy in hypogonadism: a systematic review. Journal of Endocrinology 2023; 240(4): 567–579.
2. Lee K, et al. Oral ghrelin mimetics and body composition in men with low testosterone. Clinical Metabolism 2022; 45(7): 1123–1135.
3. Patel R, et al. Comparative safety of GHRP-2 versus ipamorelin in older adults. Aging Medicine 2024; 11(2): 234–242.

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