Emerging peptide and neuroendocrine strategies for TRT-induced reproductive suppression and functional male hypogonadism: a narrative review
TL;DR
Current evidence suggests that peptide-based therapies may support endogenous hormonal signaling through targeted activation of the HPT axis, however, direct evidence demonstrating restoration of spermatogenesis or fertility following TRT-induced suppression remains limited, and important questions regarding long-term efficacy, safety, treatment protocols, and patient selection remain unresolved.
Abstract
The growing burden of male hypogonadism has raised concerns regarding the potential impact of modern lifestyles and environmental exposures on male reproductive health. Testosterone replacement therapy (TRT) is widely used for the treatment of male hypogonadism. However, prolonged TRT may suppress the hypothalamic-pituitary-testicular (HPT) axis, resulting in reduced gonadotropin production, decreased intratesticular testosterone levels, impaired spermatogenesis, testicular atrophy, and compromised fertility. Current management strategies, including human chorionic gonadotropin (hCG), follicle-stimulating hormone (FSH), and selective estrogen receptor modulators (SERMs), can support recovery in some patients, but their effectiveness remains variable. This narrative review examines the emerging role of peptide and neuroendocrine strategies in TRT-induced reproductive suppression and functional male hypogonadism. A structured literature search was conducted to identify experimental, translational, and clinical studies investigating reproductive peptides and related neuroendocrine pathways. Particular attention was given to kisspeptin-based therapies, gonadotropin-releasing hormone (GnRH)-related approaches, neurokinin signaling pathways, and other developing interventions with potential relevance to male reproductive health. Current evidence suggests that peptide-based therapies may support endogenous hormonal signaling through targeted activation of the HPT axis. However, direct evidence demonstrating restoration of spermatogenesis or fertility following TRT-induced suppression remains limited, and important questions regarding long-term efficacy, safety, treatment protocols, and patient selection remain unresolved. Emerging peptide therapeutics represent a growing area of interest in reproductive endocrinology and may expand future treatment options for selected patients. Nevertheless, further well-designed clinical studies are required to establish their long-term efficacy, safety, and role in restoring reproductive function following TRT-induced suppression.