Molecular mechanisms of clinical heterogeneity in primary dysmenorrhea

V Kutsenko, Pavel Vasilievich Seliverstov, N. Tatarova, M. Oganezova, D. Gairabekova, A. Katkova
In: Molekulyarnaya Meditsina (Molecular medicine) · 2026 · vol. 24(5) , pp. 126 · doi:10.29296/24999490-2026-05-17 · W7225598016
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This review links primary dysmenorrhea heterogeneity to distinct molecular mechanisms, noting that NGF and IL1 loci associated with chronic pain susceptibility are also endometriosis loci.

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This critical narrative review examines the molecular mechanisms underlying clinical heterogeneity in primary dysmenorrhea, focusing on pain severity, systemic symptoms, and NSAID response. The authors identify a primary pathway involving progesterone withdrawal, cyclooxygenase activity, and prostaglandin F2α that explains NSAID-responsive phenotypes, while noting that resistance may involve leukotrienes or central sensitization. Genetic variants in NGF and IL1A/IL1B are highlighted as shared risk factors for both long-standing primary dysmenorrhea and endometriosis, suggesting overlapping biological susceptibility. Relevance to endometriosis: listed as one indication for GnRH antagonists, though the paper's main focus is uterine fibroids.

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Abstract

Aim. To relate data on the molecular mechanisms of primary dysmenorrhea to the main dimensions of its clinical heterogeneity: pain severity and duration, systemic symptoms, response to nonsteroidal anti-inflammatory drugs (NSAIDs), and propensity to chronic pain. Material and methods. A critical narrative review of publications indexed in PubMed/MEDLINE in 2015 – 2026, supplemented with key earlier studies and Russian-language sources. Supporting, candidate, experimental, contradictory, and negative signals were considered separately. Key points. The strongest human evidence supports the axis “progesterone withdrawal – cyclooxygenase cascade – prostaglandin F2α/FP receptor – myometrial contractility”, which underlies the NSAID-responsive phenotype. NSAID resistance, reported by about 18% of patients, has been linked to non-prostaglandin lipid mediators (leukotrienes, platelet-activating factor, 12-HETE) and to central sensitization. The vascular component, including the NO–cGMP pathway, appears to be severity-dependent: Doppler abnormalities have been reported in pronounced but not in mild dysmenorrhea. Variants in NGF, IL1A/IL1B, BDNF, and OPRM1 together with neuroimaging data link susceptibility to a phenotype of long-standing and widespread pain; however, the NGF and IL1 loci are also endometriosis loci. Vasopressin, redox, metabolomic, and extracellular matrix signals remain candidate or contradictory. Conclusion. The clinical heterogeneity of primary dysmenorrhea cannot be explained by a single molecular mechanism. We propose an evidence map linking clinical features to molecular axes and the design of a pilot feasibility study with strict exclusion of secondary dysmenorrhea, menstrual effluent sampling, ovulation confirmation, and repeated cycle-specific measurements.
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Material

and methods. A critical narrative review of publications indexed in PubMed/MEDLINE in 2015 – 2026, supplemented with key earlier studies and Russian-language sources. Supporting, candidate, experimental, contradictory, and negative signals were considered separately. Key points. The strongest human evidence supports the axis “progesterone withdrawal – cyclooxygenase cascade – prostaglandin F2α/FP receptor – myometrial contractility”, which underlies the NSAID-responsive phenotype. NSAID resistance, reported by about 18% of patients, has been linked to non-prostaglandin lipid mediators (leukotrienes, platelet-activating factor, 12-HETE) and to central sensitization. The vascular component, including the NO–cGMP pathway, appears to be severity-dependent: Doppler abnormalities have been reported in pronounced but not in mild dysmenorrhea. Variants in NGF, IL1A/IL1B, BDNF, and OPRM1 together with neuroimaging data link susceptibility to a phenotype of long-standing and widespread pain; however, the NGF and IL1 loci are also endometriosis loci. Vasopressin, redox, metabolomic, and extracellular matrix signals remain candidate or contradictory. Conclusion. The clinical heterogeneity of primary dysmenorrhea cannot be explained by a single molecular mechanism. We propose an evidence map linking clinical features to molecular axes and the design of a pilot feasibility study with strict exclusion of secondary dysmenorrhea, menstrual effluent sampling, ovulation confirmation, and repeated cycle-specific measurements.

Keywords

dysmenorrhea, prostaglandins, leukotrienes, nitric oxide, central nervous system sensitization, biomarkers Для цитирования: Kutsenko V.P., Seliverstov P.V., Tatarova N.A., Oganezova M.S., Gairabekova D.M., Katkova A.O. Molecular mechanisms of clinical heterogeneity in primary dysmenorrhea . Молекулярная медицина. DOI: 10.29296/24999490-2026-05-17 DOI: 10.29296/24999490-2026-05-17 Список литературы: - Özcan H., Albana J., Yarde F., Dekker J., Roos E., Goverde A.J., van Dorp W., Ortiz M., Hewitt G., Simms-Cendan J., Al-Jefout M., Cooper N., Huirne J.A.F., de Leeuw R., Burger N. Definition and criteria for diagnosing primary dysmenorrhea: a modified Delphi procedure. J. Pediatr Adolesc Gynecol. 2026; 39 (2): 189–95. DOI: 10.1016/j.jpag.2025.11.007 - 2. Burnett M. Guideline No. 345: Primary dysmenorrhea. J. Obstet Gynaecol Can. 2025; 47 (5): 102840. DOI: 10.1016/j.jogc.2025.102840 - 3. Iacovides S., Avidon I., Baker F.C. What we know about primary dysmenorrhea today: a critical review. 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