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.
Keywords
Authors and affiliations
https://elibrary.ru/ldqrjk V.P. Kutsenko(1), P.V. Seliverstov(2), N.A. Tatarova(3), M.S. Oganezova(4), D.M. Gairabekova(4), A.O. Katkova(5)
1-Federal State Budgetary Educational Institution of Higher Education “Saint-Petersburg State Pediatric Medical University” of the Ministry
of Health of the Russian Federation, Litovskaya St., 2, Saint-Petersburg, 194100, Russian Federation; 2-Federal State Budgetary Military Educational Institution of Higher Education “S.M. Kirov Military Medical Academy” of the Ministry of Defence of the Russian Federation, Akademika Lebedeva St., 6, Saint-Petersburg, 194044, Russian Federation; 3-Pavlov First Saint Petersburg State Medical University,
L’va Tolstogo str., 6–8, Saint-Petersburg, 197022, Russian Federation; 4-FSBEI HE “Russian University of Medicine” of the Ministry
of Healthcare of the Russian Federation, Russian Federation, 127006, Moscow, Dolgorukovskaya St. 4; 5Federal State Autonomous
Educational Institution of Higher Education “Russian National Research Medical University named after N.I. Pirogov”
of the Ministry of Health of the Russian Federation, Ostrovityanova str., 1, build. 6, Moscow, 117513, Russian Federation
References
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. Hum Reprod Update. 2015; 21 (6): 762–78. DOI: 10.1093/humupd/dmv039
4. Dawood M.Y. Primary dysmenorrhea: advances in pathogenesis and management. Obstet Gynecol. 2006; 108 (2): 428–41. DOI: 10.1097/01.AOG.0000230214.26638.0c
5. Oladosu F.A., Tu F.F., Hellman K.M. Nonsteroidal antiinflammatory drug resistance in dysmenorrhea: epidemiology, causes, and treatment. Am. J. Obstet Gynecol. 2018; 218 (4): 390–400. DOI: 10.1016/j.ajog.2017.08.108
6. Li R., Li B., Kreher D.A., Benjamin A.R., Gubbels A., Smith S.M. Association between dysmenorrhea and chronic pain: a systematic review and meta-analysis of population-based studies. Am. J. Obstet Gynecol. 2020; 223 (3): 350–71. DOI: 10.1016/j.ajog.2020.03.002
7. Уварова Е.В., Хащенко Е.П., Юсубова В.Р. Сочетание предменструального синдрома и дисменореи у молодых женщин: особенности ведения. Эффективная фармакотерапия. 2020; 16 (7): 24–8. DOI: 10.33978/2307-3586-2020-16-7-24-28. [Uvarova E.V., Khashchenko E.P., Yusubova V.R. Sochetanie predmenstrual’nogo sindroma i dismenorei u molodykh zhenshchin: osobennosti vedeniya. Effektivnaya farmakoterapiya. 2020; 16 (7): 24–8 (in Russian)]
8. Kyathanahalli C.N., Tu F.F., Ashenafi G., Schroer M.S., Hellman K.M. Seeking the root causes of menstrual pain: a systematic review of biomarkers in menstrual effluent. Mol. Pain. 2025; 21: 17448069251360092. DOI: 10.1177/17448069251360092
9. Dmitrović R. Transvaginal color Doppler study of uterine blood flow in primary dysmenorrhea. Acta Obstet Gynecol Scand. 2000; 79 (12): 1112–6. DOI: 10.1080/00016340009169273
10. Özbay K., Semiz A. Assessment of uterine blood flow in mild primary dysmenorrhea. J. Pain Res. 2024; 17: 2071–7. DOI: 10.2147/JPR.S456239
11. Fortún-Rabadán R., Boudreau S.A., Bellosta-López P., Herrero P., Graven-Nielsen T., Doménech-Garcia V. Facilitated central pain mechanisms across the menstrual cycle in dysmenorrhea and enlarged pain distribution in women with longer pain history. J. Pain. 2023; 24 (9): 1541–54. DOI: 10.1016/j.jpain.2023.04.005
12. Lee L.C., Tu C.H., Chen L.F., Shen H.D., Chao H.T., Lin M.W., Hsieh J.C. Association of brain-derived neurotrophic factor gene Val66Met polymorphism with primary dysmenorrhea. PLoS One. 2014; 9 (11): e112766. DOI: 10.1371/journal.pone.0112766
13. Wei S.Y., Chen L.F., Lin M.W., Li W.C., Low I., Yang C.J., Chao H.T., Hsieh J.C. The OPRM1 A118G polymorphism modulates the descending pain modulatory system for individual pain experience in young women with primary dysmenorrhea. Sci Rep. 2017; 7: 39906. DOI: 10.1038/srep39906
14. Li Z., Chen J., Zhao Y., Wang Y., Xu J., Ji J., Shen J., Zhang W., Chen Z. et al. Common variants in ZMIZ1 and near NGF confer risk for primary dysmenorrhoea. Nat Commun. 2017; 8: 14900. DOI: 10.1038/ncomms14900
15. Lee C.C., Lee M.T.G., Huang I.H., Tan J., McCaw Z.R., Su K.Y., Hsu T.C., Huang R.Y.J., Kuo P.H. et al. Genome-wide association study of primary dysmenorrhea in the Taiwan Biobank validates associations near the NGF and IL1 gene loci. J. Hum Genet. 2022; 67 (8): 449–58. DOI: 10.1038/s10038-022-01023-2
16. Shang M., Liu H., Ma L., Fan T., Bai W.X., Yang J., Zhang Y., Dun W. Reinforced pain catastrophizing during menstrual phase among women with primary dysmenorrhea is mediated by cerebral blood flow in the medial prefrontal cortex. Eur. J. Neurosci. 2024; 60 (9): 6267–78. DOI: 10.1111/ejn.16545
17. Schroll J.B., Black A.Y., Farquhar C., Chen I. Combined oral contraceptive pill for primary dysmenorrhoea. Cochrane Database Syst Rev. 2023; 7 (7): CD002120. DOI: 10.1002/14651858.CD002120.pub4
18. Heger E., Szabo M., Reid-McCann R., Lucinescu I.W., Topbas Selcuki N.F., Zondervan K.T., Vincent K. The genetics of primary dysmenorrhoea: a systematic review. Reprod Fertil. 2026; 7 (3): RAF260004. DOI: 10.1530/RAF-26-0004
19. Janssen E.B., Rijkers A.C.M., Hoppenbrouwers K., Meuleman C., D’Hooghe T.M. Prevalence of endometriosis diagnosed by laparoscopy in adolescents with dysmenorrhea or chronic pelvic pain: a systematic review. Hum Reprod Update. 2013; 19 (5): 570–82. DOI: 10.1093/humupd/dmt016
20. Harmsen M.J., Van den Bosch T., de Leeuw R.A., Dueholm M., Exacoustos C., Valentin L., Hehenkamp W.J.K., Groenman F., De Bruyn C. еt al. Consensus on revised definitions of Morphological Uterus Sonographic Assessment (MUSA) features of adenomyosis: results of modified Delphi procedure. Ultrasound Obstet Gynecol. 2022; 60 (1): 118–31. DOI: 10.1002/uog.24786
21. Critchley H.O.D., Maybin J.A., Armstrong G.M., Williams A.R.W. Physiology of the endometrium and regulation of menstruation. Physiol Rev. 2020; 100 (3): 1149–79. DOI: 10.1152/physrev.00031.2019
22. Chan W.Y., Dawood M.Y., Fuchs F. Relief of dysmenorrhea with the prostaglandin synthetase inhibitor ibuprofen: effect on prostaglandin levels in menstrual fluid. Am. J. Obstet Gynecol. 1979; 135 (1): 102–8.
23. Pulkkinen M.O. Alterations in intrauterine pressure, menstrual fluid prostaglandin F levels, and pain in dysmenorrheic women treated with nimesulide. J. Clin. Pharmacol. 1987; 27 (1): 65–9. DOI: 10.1177/009127008702700110
24. Böttcher B., Laterza R.M., Wildt L., Seufert R.J., Buhling K.J., Singer C.F., Hill W., Griffin P., Jilma B., Schulz M., Smith R.P. A first-in-human study of PDC31 (prostaglandin F2α receptor inhibitor) in primary dysmenorrhea. Hum Reprod. 2014; 29 (11): 2465–73. DOI: 10.1093/humrep/deu205
25. Barcikowska Z., Grzybowska M.E., Wąż P., Jaskulak M., Kurpas M., Sotomski M., Starzec-Proserpio M., Rajkowska-Labon E., Hansdorfer-Korzon R., Zorena K. Effect of manual therapy compared to ibuprofen on primary dysmenorrhea in young women – concentration assessment of C-reactive protein, vascular endothelial growth factor, prostaglandins and sex hormones. J. Clin Med. 2022; 11 (10): 2686. DOI: 10.3390/jcm11102686
26. Fang L., Gu C., Liu X., Xie J., Hou Z., Tian M., Yin J., Li A., Li Y. Metabolomics study on primary dysmenorrhea patients during the luteal regression stage based on ultra performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry. Mol. Med. Rep. 2017; 15 (3): 1043–50. DOI: 10.3892/mmr.2017.6116
27. Royo P., Alcázar J.L. Three-dimensional power Doppler assessment of uterine vascularization in women with primary dysmenorrhea. J. Ultrasound Med. 2008; 27 (7): 1003–10. DOI: 10.7863/jum.2008.27.7.1003
28. Saribiyik Çakmak B., Çakmak A.C., Can Y., Kilic H. Assessment of endothelial dysfunction in women with primary dysmenorrhea. Scand Cardiovasc J. 2026; 60 (1): 2613540. DOI: 10.1080/14017431.2026.2613540
29. Sun M.F., Huang H.C., Lin S.C., Chang L.P., Liu C.F. Evaluation of nitric oxide and homocysteine levels in primary dysmenorrheal women in Taiwan. Life Sci. 2005; 76 (17): 2005–9. DOI: 10.1016/j.lfs.2004.09.030
30. Li Y., Yang Z., Yu B., Zhang X., Li X., Chen W., Yuan M., Sui Z., Zhang Y., Hou W., Gao D. Integrated transcriptomic and proteomic profiling implicates prostaglandin–nitric oxide network dysregulation in uterine microcirculatory impairment in primary dysmenorrhea. Front Immunol. 2026; 17: 1833346. DOI: 10.3389/fimmu.2026.1833346
31. Moya R.A., Moisa C.F., Morales F., Wynter H., Ali A., Narancio E. Transdermal glyceryl trinitrate in the management of primary dysmenorrhea. Int. J. Gynaecol Obstet. 2000; 69 (2): 113–8. DOI: 10.1016/S0020-7292(00)00185-5
32. Dmitrovic R., Kunselman A.R., Legro R.S. Sildenafil citrate in the treatment of pain in primary dysmenorrhea: a randomized controlled trial. Hum Reprod. 2013; 28 (11): 2958–65. DOI: 10.1093/humrep/det324
33. Åkerlund M. Can primary dysmenorrhea be alleviated by a vasopressin antagonist? Results of a pilot study. Acta Obstet Gynecol Scand. 1987; 66 (5): 459–61. DOI: 10.3109/00016348709022055
34. Valentin L., Sladkevicius P., Kindahl H., Broeders A., Marsal K., Melin P. Effects of a vasopressin antagonist in women with dysmenorrhea. Gynecol Obstet Invest. 2000; 50 (3): 170–7. DOI: 10.1159/000010319
35. Liedman R., Hansson S.R., Howe D., Igidbashian S., Russell R.J., Åkerlund M. Endometrial expression of vasopressin, oxytocin and their receptors in patients with primary dysmenorrhoea and healthy volunteers at ovulation. Eur. J. Obstet Gynecol Reprod Biol. 2008; 137 (2): 189–92. DOI: 10.1016/j.ejogrb.2007.10.015
36. Payne L.A., Rapkin A.J., Seidman L.C., Zeltzer L.K., Tsao J.C.I. Experimental and procedural pain responses in primary dysmenorrhea: a systematic review. J. Pain Res. 2017; 10: 2233–46. DOI: 10.2147/JPR.S143512
37. Böttcher B., Gizewski E.R., Siedentopf C., Steiger R., Verius M., Riedl D., Ischebeck A., Schmid J., Wildt L., Elsenbruch S. Behavioural and neural responses to aversive visceral stimuli in women with primary dysmenorrhoea. Eur. J. Pain. 2019; 23 (2): 272–84. DOI: 10.1002/ejp.1302
38. Tu C.H., Niddam D.M., Chao H.T., Chen L.F., Chen Y.S., Wu Y.T., Yeh T.C., Lirng J.F, Hsieh JC. Brain morphological changes associated with cyclic menstrual pain. Pain. 2010; 150 (3): 462–8. DOI: 10.1016/j.pain.2010.05.026
39. Vincent K., Warnaby C., Stagg C.J., Moore J., Kennedy S., Tracey I. Dysmenorrhoea is associated with central changes in otherwise healthy women. Pain. 2011; 152 (9): 1966–75. DOI: 10.1016/j.pain.2011.03.029
40. Yu S., Xu J., Shen Z., Wang Y., Wei W., Guo X., Tian J., Liu L., Yang Y., Zeng F., Liang F., Yang J. Frequency-specific alterations in brain function in patients with primary dysmenorrhea. Pain Med. 2022; 23 (5): 902–11. DOI: 10.1093/pm/pnab225
41. Jin P., Wang F., Zeng F., Yu J., Cui F., Yang B., Zhang L. Revealing the mechanism of central pain hypersensitivity in primary dysmenorrhea: evidence from neuroimaging. Quant Imaging Med Surg. 2024; 14 (4): 3075–85. DOI: 10.21037/qims-23-1687
42. Machado A.F.P., Perracini M.R., Rampazo E.P., Driusso P., Liebano R.E. Effects of thermotherapy and transcutaneous electrical nerve stimulation on patients with primary dysmenorrhea: a randomized, placebo-controlled, double-blind clinical trial. Complement Ther Med. 2019; 47: 102188. DOI: 10.1016/j.ctim.2019.08.022
43. Szmidt M.K., Granda D., Sicinska E., Kaluza J. Primary dysmenorrhea in relation to oxidative stress and antioxidant status: a systematic review of case-control studies. Antioxidants (Basel). 2020; 9 (10): 994. DOI: 10.3390/antiox9100994
44. Yeh M.L., Chen H.H., So E.C., Liu C.F. A study of serum malondialdehyde and interleukin-6 levels in young women with dysmenorrhea in Taiwan. Life Sci. 2004; 75 (6): 669–73. DOI: 10.1016/j.lfs.2003.11.034
45. Kazemi M., Lalooha F., Rashidi Nooshabadi M., Khadem Haghighian H. Decreased dysmenorrhea pain in girls by reducing oxidative stress and inflammatory biomarkers following supplementation with oleoylethanolamide: a randomized controlled trial. J. Obstet Gynaecol Res. 2022; 48 (5): 1212–21. DOI: 10.1111/jog.15196
46. Su S., Duan J., Wang P., Liu P., Guo J., Shang E., Qian D., Tang Y., Tang Z. Metabolomic study of biochemical changes in the plasma and urine of primary dysmenorrhea patients using UPLC-MS coupled with a pattern recognition approach. J. Proteome Res. 2013; 12 (2): 852–65. DOI: 10.1021/pr300935x
47. Sun Y., Chu J.Z., Geng J.R., Guan F.L., Zhang S.C., Ma Y.C., Zuo Q.Q., Jing X.Z., Du H.L. Label-free based quantitative proteomics analysis to explore the molecular mechanism of gynecological cold coagulation and blood stasis syndrome. Anat Rec (Hoboken). 2023; 306 (12): 3033–49. DOI: 10.1002/ar.25035
48. Donayeva A., Amanzholkyzy A., Nurgaliyeva R., Gubasheva G., Saparbayev S., Ayaganov D., Kaldybayeva A., Abdelazim I.A., Farghali M.M. Vitamin D and vitamin D receptor polymorphism in Asian adolescents with primary dysmenorrhea. BMC Womens Health. 2023; 23: 414. DOI: 10.1186/s12905-023-02569-9
49. Геворгян А.П., Аракелян А.С., Адамян Л.В. Роль эндотелиальной дисфункции в патогенезе первичной дисменореи у девочек-подростков. Проблемы репродукции. 2021; 27 (5): 62–70. DOI: 10.17116/repro20212705162. [Gevorgyan A.P., Arakelyan A.S., Adamyan L.V. Rol’ endotelial’noi disfunktsii v patogeneze pervichnoi dismenorei u devochek-podrostkov. Problemy reproduktsii. 2021; 27 (5): 62–70 (in Russian)]
50. Eldridge S.M., Chan C.L., Campbell M.J., Bond C.M., Hopewell S., Thabane L., Lancaster G.A. PAFS consensus group. CONSORT 2010 statement: extension to randomised pilot and feasibility trials. BMJ. 2016; 355: i5239. DOI: 10.1136/bmj.i5239