Orexins Modulate Testicular Function, Regulating Spermatogenesis, Steroidogenesis, and Glucose Metabolism

The testis is under complex neuroendocrine control, crucial for male fertility and overall reproductive health. While hypothalamic neuropeptides like orexins are well-known for their roles in the sleep-wake cycle, food intake, and energy balance, their specific contributions to testicular function have been increasingly recognized. Current understanding often overlooks the intricate auto/paracrine actions of these neuropeptides within the gonad itself. This review addresses the gap by consolidating knowledge on how the orexin system directly impacts various aspects of male reproductive physiology, moving beyond its central nervous system functions.

This review article systematically synthesized existing literature on the orexin system's role in male gonadal function. Researchers analyzed studies exploring the mechanisms by which orexin A (OXA) and orexin B (OXB), along with their G-protein-coupled receptors, OX1R and OX2R, influence testicular processes. The scope included investigations into steroidogenesis, germ cell dynamics, glucose metabolism, and oxidative stress responses within the testis. The primary objective was to consolidate current knowledge and identify gaps in understanding the neuroendocrine control of spermatogenesis, providing a comprehensive overview of the orexin system's peripheral actions.

The comprehensive review revealed that the orexin system is a multifaceted regulator of testicular physiology, acting both as a neuroendocrine signal and through local auto/paracrine mechanisms. Orexins, primarily acting via OX1R and OX2R expressed in various testicular cells, significantly influence steroidogenesis, impacting the biosynthesis and secretion of crucial male hormones like testosterone. Furthermore, the system plays a vital role in germ cell dynamics, affecting the proliferation, differentiation, and maturation of sperm, which is fundamental for successful spermatogenesis.

Orexins were consistently shown to modulate glucose metabolism within the testis, suggesting a direct link to energy supply for germ cell development and function, and to influence oxidative stress responses, which are critical for maintaining testicular health and protecting against cellular damage.

The review highlighted the intricate interplay between the hypothalamus and the testis, underscoring the importance of the orexin system in integrating central metabolic signals with local testicular regulation.