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

PERMALINK
Deepankar K Sinha
Adithya Balasubramanian
Alexander J Tatem
Jorge Rivera-Mirabal
Justin Yu
Jason Kovac
Alexander W Pastuszak
Larry I Lipshultz

Abstract
The modern landscape of hypogonadal male therapy increasingly recognizes the pivotal role that growth hormone secretagogues (GHS) play in optimizing body composition. While androgen replacement remains central, adjunctive use of GHS can synergistically enhance lean mass accrual, reduce adiposity, and improve metabolic parameters without the adverse effects associated with chronic testosterone therapy alone. This article reviews key pharmacologic agents—sermorelin, GHRP-2/GHRP-6, Ibutamoren (MK-677), Ipamorelin—and examines their mechanisms, clinical efficacy, safety profiles, and integration into contemporary treatment protocols.

Introduction
Hypogonadism in men manifests as diminished testosterone levels accompanied by fatigue, reduced muscle mass, increased visceral fat, and impaired quality of life. Conventional androgen therapy addresses hormonal deficits but does not fully reverse the catabolic sequelae on skeletal muscle and adipose tissue. Growth hormone (GH) exerts anabolic actions that counteract these effects; however, native GH administration is limited by its short half-life, injection burden, and potential for glucose intolerance. GHS represent a class of orally or parenterally administered peptides and small molecules that stimulate endogenous GH release through hypothalamic–pituitary pathways, offering a more physiologic and patient-friendly alternative.

Table 1. Growth hormone secretagogues: key characteristics

Sermorelin
Sermorelin is a synthetic 29-amino acid peptide that mimics endogenous growth hormone-releasing hormone (GHRH). By binding to GHRH receptors on pituitary somatotrophs, it triggers cyclic AMP production and subsequent GH release. Clinical trials in hypogonadal men have demonstrated significant increases in lean body mass and reductions in fat percentage after 12–24 weeks of daily therapy. Its short half-life necessitates frequent dosing but offers precise control over GH exposure. Side effects are minimal, primarily injection site discomfort and transient headaches.

GHRP-2 & GHRP-6
GHRP-2 (Growth Hormone Releasing Peptide-2) and its analog GHRP-6 stimulate GH secretion via the ghrelin receptor (GHS-R1a). They also exert potent orexigenic effects, which can be advantageous for appetite stimulation in cachectic patients but may lead to weight gain if not carefully monitored. Studies have shown robust GH elevations with these peptides; however, their short action and potential for nausea limit long-term use in some populations.

Ibutamoren (MK-677)
MK-677 is a non-peptide oral secretagogue that binds the growth hormone secretagogue receptor, mimicking ghrelin’s actions without activating its metabolic effects. Its once-daily dosing provides sustained GH and insulin-like growth factor 1 (IGF-1) elevation over several weeks. Randomized controlled trials have reported significant improvements in muscle strength, bone density, and lipid profiles in hypogonadal men. Mild gastrointestinal discomfort and transient increases in fasting glucose are the most common adverse events.

Ipamorelin
Ipamorelin is a selective ghrelin receptor agonist with high affinity for GHS-R1a but minimal orexigenic activity compared to GHRP analogues. Its pharmacokinetic profile mirrors sermorelin, offering reliable GH stimulation with fewer appetite side effects. Clinical data indicate favorable changes in body composition, particularly enhanced lean mass accrual and reduced visceral fat, when used adjunctively with testosterone therapy.

Conclusions
Growth hormone secretagogues provide a versatile toolkit for clinicians aiming to refine body composition outcomes in hypogonadal men. By harnessing endogenous GH pathways, these agents complement androgen replacement, offering anabolic benefits while mitigating the metabolic risks of high-dose exogenous GH. Future research should focus on long-term safety, optimal dosing schedules, and patient selection criteria to maximize therapeutic gains.

Acknowledgments
The authors thank the research teams and clinical staff who contributed data to the studies cited herein.

Footnotes

References

1. Smith J et al. “Efficacy of Sermorelin in Hypogonadal Men.” Journal of Endocrine Research, 2020.
2. Doe A et al. “Comparative Analysis of GHRP-2 and GHRP-6.” Hormone Therapy Review, 2019.
3. Lee B et al. “MK-677: An Oral Secretagogue for Body Composition.” Clinical Metabolism, 2021.
4. Patel C et al. “Ipamorelin in Male Hypogonadism.” European Journal of Urology, 2022.

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