Neuroreproductive axis disruptions in early childhood: Unveiling hidden links between pediatric inflammation and future fertility risks (A literature review)

Relevance: The neuroreproductive axis, regulated by the hypothalamic-pituitary-gonadal (HPG) system, is critical for reproductive development and function. Early-life inflammation due to maternal immune activation, obesity, or infection can disrupt this axis, potentially impairing fertility and endocrine function later in life. This study aimed to explore how pediatric inflammation affects neuroendocrine programming and reproductive outcomes. Materials and Methods: A multidisciplinary review of clinical, epidemiological, and animal model studies was conducted to examine associations between early-life immune activation and later reproductive outcomes. Focus was placed on cytokine signaling (e.g., IL-6, TNF-α), hypothalamic development, and epigenetic modifications affecting GnRH and gonadotropin regulation. Results: Findings reveal that inflammation during fetal and early childhood periods alters GnRH neuron migration and function. Elevated maternal or pediatric cytokines cross the blood-brain barrier, disrupt HPG signaling, and induce epigenetic changes in reproductive genes. These disruptions are associated with delayed puberty, altered menstrual cycles, reduced sperm quality, and conditions like PCOS. Chronic low-grade inflammation from childhood obesity further exacerbates reproductive hormone dysregulation. Conclusions: Early-life inflammation emerges as a key disruptor of neuroreproductive development, with long-term effects on fertility, metabolism, and mental health. Identifying critical windows of vulnerability and implementing early screening may help prevent or mitigate long-term endocrine and reproductive dysfunction. These findings underscore the developmental origins of adult reproductive health and support targeting early-life inflammation as a strategy to improve future fertility outcomes.