From “Passive Supplementation” to “Active Repair”: Melatonin Reshapes the Treatment Paradigm for Late‐Onset Hypogonadism by Targeting Leydig Cell Senescence

In the context of global population aging, public health challenges due to aging are garnering significant attention. Late-onset hypogonadism (LOH) is a common age-related condition in men characterized by progressively decreasing serum testosterone levels with age, manifesting as sexual dysfunction, reduced physical vigor, and psychological or neurological abnormalities. Testosterone is synthesized primarily in testicular Leydig cells (LCs), and LC senescence during aging is key for suppressing testosterone production. This review systematically synthesizes the multidimensional molecular mechanisms underlying LC senescence. This process is driven primarily by oxidative stress (OS) and mitochondrial dysfunction and encompasses multiple interrelated layers, including epigenetic remodeling, the senescence-associated secretory phenotype (SASP), stem Leydig cell (SLC) niche degradation, and disruption of intrinsic circadian rhythms. Exogenous testosterone supplementation therapy (TST) remains the mainstay of the clinical management of LOH; however, its long-term use increasingly poses safety risks and is inherently limited to treating symptoms. Melatonin, a molecule with pleiotropic antiaging properties, including potent antioxidant effects and the ability to improve mitochondrial function, has the potential to synergistically antagonize the aforementioned multiple LC senescence pathways. By effectively mitigating LC aging and promoting endogenous testosterone synthesis, the use of melatonin could shift the treatment paradigm for LOH from "passive hormone supplementation" to "active cellular function repair". This article recapitulates preclinical and preliminary clinical evidence on the efficacy of melatonin in treating testicular or LC dysfunction, validating its therapeutic promise, and proactively identifies critical directions for future translational research, providing valuable insights for the development of novel, etiology-oriented therapeutic strategies for LOH.