Male testosterone synthesis disorders: oxidative stress pathways, regulatory mechanisms, potential of antioxidant therapy, and botanical medicine prospects

Testosterone, one of the most important hormones in men, regulates many physiological and pathological processes. Testosterone biosynthesis mainly occurs in Leydig cells. Oxidative stress (OS) is also commonly observed in Leydig cells and is an important factor, leading to decreased testosterone concentrations. This review evaluates male testosterone synthesis disorders from the perspective of OS. OS impairs testosterone synthesis through multiple mechanisms, including modulating the function of the hypothalamic-pituitary-gonadal axis, reducing testicular steroid synthase activity, damaging the mitochondrial function of Leydig cells, inducing endoplasmic reticulum stress, and inhibiting Leydig cell development. A coordinated regulatory network comprising nuclear factor erythroid-2-related factor 2 (Nrf2), sirtuin 1 (SIRT1), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 α ), and the glutathione pathway, plays an integral role in modulating testosterone biosynthesis. We summarize the therapeutic potential of antioxidants, especially botanical medicines, in mitigating Leydig cell oxidative injury and restoring testosterone biosynthesis, highlighting their promise as a novel treatment approach. Finally, the therapeutic potential of antioxidants in male disorders of testosterone synthesis, including late-onset hypogonadism, male infertility, and erectile dysfunction, is systematically reviewed and critically analyzed. This review provides a deeper understanding of the mechanisms underpinning testosterone synthesis disorders and may facilitate the development of new clinical treatments.