The hormone-microbiota-NET framework in gynecologic diseases: evidence, controversies, and translational opportunities

Gynecologic diseases, including infectious disorders, endocrine-related conditions, gynecologic malignancies, and pregnancy complications, are clinically diverse yet frequently share features of hormonal imbalance, microbial dysbiosis, and dysregulated inflammation. Current research has largely examined these processes separately, limiting integrated understanding of their potential interactions. This review synthesizes current evidence and proposes a hormone-microbiota-neutrophil extracellular trap (NET) framework as a conceptual tool for understanding common and disease-specific mechanisms across gynecologic disorders. We first summarize the core molecular basis of NET formation, with emphasis on peptidylarginine deiminase 4 as a candidate regulatory node. We then examine the effects of sex hormones on NET regulation, the role of the microbiota in shaping mucosal immune responses, and potential mechanistic links between microbial products, extracellular matrix components, and NET dysregulation. Evidence is further integrated across representative infectious, endocrine-related, malignant, and pregnancy-associated conditions, including pelvic inflammatory disease, bacterial vaginosis, endometriosis, polycystic ovary syndrome, ovarian, cervical, and endometrial cancers, and preeclampsia. The available literature indicates that hormone-dependent immune modulation, pathogen- or microbiota-associated inflammatory signaling, and NET-related tissue injury may converge in multiple gynecologic settings, although the strength of evidence differs substantially across specific pathways and diseases. Direct support is strongest for selected hormone-NET effects in defined experimental or pregnancy-associated settings and for pathogen/microbial product-NET interactions in infectious contexts, whereas the complete hormone-microbiota-NET framework and the proposed glycosaminoglycan-peptidylarginine deiminase 4 (GAG-PAD4) bridge remain insufficiently validated. Overall, this review provides an evidence-based integrative framework for organizing current knowledge, identifying mechanistic gaps, and informing future biomarker development, patient stratification, and translational research in gynecologic disease.