Seeking the root causes of menstrual pain: A systematic review of biomarkers in menstrual effluent.

Dysmenorrhea (period pain) affects over 40% of women and is a leading cause of missed school and workdays. However, the molecular mechanisms underlying this pain are not fully understood. We conducted a systematic review (Prospero registration: CRD42024535081) to identify and evaluate the biomolecules in menstrual effluent that may contribute to dysmenorrhea and assess how non-hormonal medications (e.g. NSAIDs) impact these biomarkers. Fifteen studies involving two hundred twenty-three participants met the inclusion criteria. We used the Newcastle-Ottawa Scale (for observational studies) and the Cochrane RoB2 tool (for randomized controlled trials) to evaluate the risk of bias and the quality of studies. Eight studies consistently reported elevated prostaglandin levels in the menstrual effluent of women with dysmenorrhea, though sample sizes were generally small, and methodological issues were noted. Seven studies demonstrated that NSAIDs reduce prostaglandin concentrations; however, these trials utilized multiple-day dosing protocols instead of single-dose regimens, leaving questions about acute treatment effects. Two studies highlighted alternative molecular targets, such as 12-HETE and platelet-activating factor (PAF), that may also play key roles in menstrual pain. Overall, elevated prostaglandins are a recurring finding, but the limited scope and design of existing studies indicate a need for larger, methodologically rigorous investigations. Nevertheless, the few studies that identified molecules other than prostaglandins suggest there are viable druggable targets for clinical trials to reduce menstrual pain.