Hormonal and Inflammatory Mechanisms of Dysmenorrhea and Implications for Targeted, Multimodal Management: An Updated Narrative Review

Objectives: To synthesize updated evidence on hormonal, inflammatory, oxidative, and neuroimmune mechanisms driving primary and secondary dysmenorrhea; clarify endocrine–immune crosstalk (progesterone withdrawal, COX-2–prostaglandin axis, cytokine networks, vasopressin/oxytocin signaling); and identify mechanistic targets supporting personalized, targeted, and multimodal therapeutic strategies for clinical translation. Methods: A PRISMA-adapted narrative review (2010–2025) was conducted using PubMed, Scopus, and Web of Science. Peer-reviewed English full texts addressing mechanistic biomarkers, uterine contractility, pain pathways, or treatment-linked mechanisms were included. Heterogeneous clinical, observational, and experimental evidence was thematically synthesized; risk of bias was assessed using design-appropriate tools. Results: Across 29 studies, dysmenorrhea consistently reflected progesterone withdrawal–driven COX-2 upregulation and excess PGF₂α/PGE₂, producing uterine hypercontractility, vasoconstriction, and ischemic pain. Proinflammatory cytokines (IL-1β, IL-6, TNF-α) amplified prostaglandin synthesis and nociceptor excitability, while leukotriene signaling emerged as an adjunct inflammatory axis in severe cases. Oxidative stress (increased MDA, decreased SOD/GPx) and nitric oxide dysregulation impaired uterine perfusion. Neuroimmune sensitization and lowered pain thresholds suggested central processing contributions. Therapeutic implications supported multimodal combinations: NSAIDs/hormonal suppression plus antioxidants, exercise, and selected adjuncts targeting LOX/cytokines. Conclusion: Dysmenorrhea is best conceptualized as a cyclic neuroendocrine–inflammatory disorder rather than isolated uterine hypercontractility. Mechanistic convergence across prostanoids, cytokines, oxidative imbalance, and sensitization supports layered, multimodal care. Future biomarker-stratified trials should test targeted combinations (COX/LOX modulation, endocrine stabilization, redox support, neuroimmune approaches) to improve efficacy and tolerability.