From uterus to brain: the NEIF hypothesis-a multi-layered framework for primary dysmenorrhea pathogenesis and emerging biomarkers

Primary dysmenorrhea (PD) affects 50-90% of women but remains understudied and inadequately managed. The conventional prostaglandin (PG)-centric model incompletely explains non-steroidal anti-inflammatory drug (NSAID) non-response-which is multifactorial and not mechanistically specific-and lowered pain thresholds outside menstruation. We propose the neuroendocrine-inflammatory framework (NEIF), a testable, hypothesis-generating framework rather than an established pathogenic cascade. NEIF views PD as multilayered: progesterone withdrawal and PG dysregulation; cytokine/NF-κB amplification; oxidative stress; peripheral sensitization; central plasticity; and genetic/epigenetic susceptibility. Evidence strength varies, from direct human and replicated genetic data to correlative, neuroimaging, or preclinical evidence. A speculative NOD-like receptor protein 3 (NLRP3) inflammasome-pyroptosis extension is not a core NEIF level or candidate endotype because direct human PD evidence is absent; it is an evidence-gated validation gap. Candidate biomarkers include menstrual-effluent oxylipins, serum nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF), neuroimaging intermediate phenotypes, and genetic variants; none is clinically qualified. NEIF yields three research-only candidate mechanistic endotypes-PG-predominant, inflammatory-oxidative, and neurogenic-central-not a clinical classification. It reframes PD as systemic and provides testable hypotheses while direct human NLRP3 validation remains desirable but not required for the core framework.