Abstract

The gut–brain–gonadal (GBG) axis represents a complex bidirectional network integrating endocrine, neural, and 
immune signals to regulate homeostasis. Emerging evidence indicates that dysregulation of reproductive hormones, 
such as estrogens, progesterone, and androgens, intersects with oxidative stress and immune signaling to exacerbate 
neurotoxicity. Disturbances in the gut microbiota, altered hypothalamic–pituitary–gonadal (HPG) axis activity, and 
chronic systemic inflammation converge to disrupt neuronal survival, synaptic plasticity, and neuroendocrine 
balance. Reactive oxygen species (ROS) and reactive nitrogen species (RNS) promote DNA damage, mitochondrial 
dysfunction, and lipid peroxidation, while immune mediators including cytokines, Toll-like receptors, and microglial 
activation amplify neuroinflammatory cascades. Hormonal fluctuations-particularly hypoestrogenism, androgen 
deficiency, and altered gonadotropin secretion-further modulate oxidative and immune pathways, heightening 
susceptibility to neurodegeneration, mood disorders, and reproductive dysfunction. This review synthesizes 
mechanistic insights into the interplay of oxidative stress and immunomodulation within the GBG axis, highlighting 
their roles in neurotoxicity and endocrine disruption. It also discusses therapeutic implications, including 
microbiota-targeted strategies, antioxidants, and immunomodulatory agents that may restore axis homeostasis and 
mitigate disease progression. 
Keywords: neurotoxicity, reproductive hormones, oxidative stress, immunomodulation, gut-brain-gonadal axis