A Narrative Review of Recent Insights on Nerve Growth Factor Signaling in Physiological and Pathological Ovarian...

Nerve Growth Factor (NGF), a member of the neurotrophin family, is currently regarded as a key regulator of ovarian physiology beyond its well-known neurotrophic functions. The mammalian ovary is one of the most highly innervated peripheral organs. Increasing evidence indicates that NGF and its receptors, TrkA and p75NTR, are widely expressed in ovarian tissues. Through the activation of the PI3K/AKT, MAPK/ERK, and PLCγ signaling pathways, NGF influences granulosa cell proliferation, steroidogenesis, and ovulation. Physiological levels of NGF are essential for primordial follicle activation, FSH receptor expression, and effective bidirectional communication between oocytes and surrounding somatic cells. As a result, NGF also regulates oocyte maturation and developmental competence. The disruption of NGF signaling can lead to serious health issues. Both low and high levels of NGF negatively affect folliculogenesis and fertility. Elevated intraovarian NGF results in sympathetic over-innervation, altered steroid production, and polycystic ovarian features. In addition, increased NGF expression has been linked to endometriosis and ovarian cancer progression. Clinical studies further suggest that follicular NGF levels may serve as indicators of ovarian reserve and reproductive outcomes in assisted reproduction. This narrative review synthesizes the current knowledge on NGF roles in ovarian physiology and disease. It highlights NGF' dual functions as a central regulator of follicular dynamics, and as a potential biomarker and therapeutic target for common reproductive system diseases.