Looking ahead: new approaches to the diagnosis, treatment, and rehabilitation of patients with deep infiltrating endometriosis

Deep infiltrating endometriosis (DIE) is a severe form of endometriosis characterized by deep infiltration of endometriotic tissue into the retroperitoneal space and muscular walls of pelvic organs. Its nonspecific clinical presentation and the limited sensitivity of standard diagnostic methods contribute to significant diagnostic delays, while current treatments are primarily symptomatic and associated with high recurrence rates. This review summarizes current and emerging approaches to the diagnosis of DIE, including molecular markers, high-resolution imaging techniques, standardized protocols and classifications, and artificial intelligence-based algorithms. Potential therapeutic targets involved in the pathogenesis of DIE are discussed, including the PI3K/Akt/mTOR signaling pathway, microRNAs, fibrogenic factors, and specific immune mechanisms. Particular attention is given to multidisciplinary rehabilitation strategies, such as physiotherapy, exercise, nutritional and psychological support, and modulation of the vaginal and gut microbiota. Further advances in the diagnosis, treatment, and rehabilitation of patients with DIE are needed to facilitate earlier diagnosis, enable personalized therapy, and improve long-term clinical outcomes. About the Authors S. V. KhlopkovaRussian Federation Svetlana V. Khlopkova 2/44 Salyam Adil Str., Moscow 123423 A. Yu. Shatilina Russian Federation Anastasia Yu. Shatilina Scopus Author ID: 59334355900 8 bldg 2 Trubetskaya Str., Moscow 119048 N. A. Martirosyan Russian Federation Naira A. Martirosyan 8 bldg 2 Trubetskaya Str., Moscow 119048 M. R. Khadanovich Russian Federation Margarita R. Khadanovich 8 bldg 2 Trubetskaya Str., Moscow 119048 K. V. Lazareva Russian Federation Ksenia V. Lazareva 8 bldg 2 Trubetskaya Str., Moscow 119048 K. N. Grigoryeva Russian Federation Kristina N. Grigoryeva, PhD, Assoc. Prof. Scopus Author ID: 57218340109 8 bldg 2 Trubetskaya Str., Moscow 119048 J. Kh. Khizroeva Russian Federation Jamilya Kh. Khizroeva, Dr. Sci. Med., Prof. WoS ResearcherID: F-8384-2017. Scopus Author ID: 57194547147 8 bldg 2 Trubetskaya Str., Moscow 119048 A. G. Solopova Russian Federation Antonina G. Solopova, Dr. Sci. Med., Prof. WoS ResearcherID: Q-1385-2015. Scopus Author ID: 6505479504 8 bldg 2 Trubetskaya Str., Moscow 119048

1. Martire F.G., Raimondo D., Raffone A., et al. Deep infiltrating endometriosis in adolescence: early diagnosis and possible prevention of disease progression. J Сlin Med. 2024; 13 (2): 550. https://doi.org/10.3390/jcm13020550. 2. Abike F., Tanoglu F.B., Sidar G. Deep pelvic endometriosis: clinical features, diagnosis, and treatment – a comprehensive review. Arch Gynecol Obstet. 2025; 312 (6): 1857–69. https://doi.org/10.1007/s00404-025-08187-0. 3. Osaki J.D., Oliveira M.A.P. What is behind? Impact of pelvic pain on perceived stress and inflammatory markers in women with deep endometriosis. J Сlin Med. 2024; 13 (10): 2927. https://doi.org/10.3390/jcm13102927. 4. Yela D.A., Silva M.S.S., Eloy L., Benetti-Pinto C.L. Correlation between anatomopathological aspects and pelvic pain in women with deep infiltrating endometriosis. Rev Bras Ginecol Obstet. 2023; 45 (12): e770–4. https://doi.org/10.1055/s-0043-1772473. 5. Chernetsova A.S., Adamyan L.V., Murvatov K.D., Stepanian A.A. Pathogenetic aspects of chronic pelvic pain in endometriosis: diagnostic prospects (literature review). Russian Journal of Human Repro- duc tion. 2024; 30 (4): 112–20 (in Russ.). https://doi.org/10.17116/repro202430041112. 6. Orazov M.R., Mihaleva L.M., Bekulova M.A. Infiltrative endometriosis and adhesions: is there a cause-and-effect relationship? Gynecology. 2021; 23 (2): 198–204 (in Russ.). https://doi.org/10.26442/20795696.2021.2.200743. 7. Shifon S., Tyrinova T., Veretelnikova T., et al. Endometriosis as an immune-mediated disease: pathogenetic mechanisms and therapeutic strategies. Front Immunol. 2025; 16: 1727183. https://doi.org/10.3389/fimmu.2025.1727183. 8. Edi R., Cheng T. Endometriosis: evaluation and treatment. Am Fam Physician. 2022; 106 (4): 397–404. 9. Simons M., Cline M., Gubbels A., et al. Endometriosis is associated with higher healthcare utilization and upper gastrointestinal symptoms. Clin Gastroenterol Hepatol. 2024; 22 (10): 2143–6.e1. https://doi.org/10.1016/j.cgh.2024.03.005. 10. Mabrouk M., Del Forno S., Spezzano A., et al. Painful love: superficial dyspareunia and three dimensional transperineal ultrasound evaluation of pelvic floor muscle in women with endometriosis. J Sex Marital Ther. 2020; 46 (2): 187–96. https://doi.org/10.1080/0092623X.2019.1676852. 11. Orr N.L., Noga H., Liu Y.T., et al. Deep dyspareunia in endometriosis: role of the bladder and pelvic floor. J Sex Med. 2018; 15 (8): 1158–66. https://doi.org/10.1016/j.jsxm.2018.06.007. 12. Orazov M.R., Radzinsky V.E., Mikhaleva L.M., et al. Dyspareunia as a hallmark of infiltrative forms of endometriosis. Trudnyj Pacient / Difficult Patient. 2021; 19 (1): 18-22. https://doi.org/10.24412/20741995-2021-1-18-22. 13. Saponara S., Scicchitano F., D’Alterio M.N., et al. Could the estrobolome have a role in endometriosis pathogenesis and infertility? A systematic review. BMC Women's Health. 2026; 26 (1): 43. https://doi.org/10.1186/s12905-025-04195-z. 14. Zondervan K.T., Becker C.M., Koga K., et al. Endometriosis. Nat Rev Dis Primers. 2018; 4 (1): 9. https://doi.org/10.1038/s41572-018-0008-5. 15. Piriyev E., Schiermeier S., Römer T. Hormonal treatment of endometriosis: a narrative review. Pharmaceuticals. 2025; 18 (4): 588. https://doi.org/10.3390/ph18040588. 16. Horne A.W., Missmer S.A. Pathophysiology, diagnosis, and management of endometriosis. BMJ. 2022; 379: e070994. https://doi.org/10.1136/bmj-2022-070994. 17. Facchin F., Barbara G., Saita E., et al. Mental health in women with endometriosis: searching for predictors of psychological distress. Hum Reprod. 2015; 30 (5): 1119–25. https://doi.org/10.1093/humrep/dev066. 18. Márki G., Bokor A., Rigó J., Rigó A. Physical pain and emotion regulation as the main predictive factors of health-related quality of life in women living with endometriosis. Hum Reprod. 2017; 32 (7): 1432–8. https://doi.org/10.1093/humrep/dex091. 19. Lisá Z., Fanta M., Kokavec J., Janoštiak R. Global RNA expression analysis of patient samples identified potential diagnostic biomarkers specific for peritoneal, ovarian and deep endometriosis. Sci Rep. 2026; 16 (1): 5070. https://doi.org/10.1038/s41598-026-35467-9. 20. Situmorang H., Pramayadi C.T., Kurniawan R.H., et al. Unraveling molecular heterogeneity: a systematic review of susceptibility gene profiles in ovarian, deep infiltrating, and superficial peritoneal endometriosis. Front Reprod Health. 2026; 8: 1749020. https://doi.org/10.3389/frph.2026.1749020. 21. Dryja-Brodowska A., Obrzut B., Obrzut M., Darmochwał-Kolarz D. miRNA in endometriosis – a new hope or an illusion? J Clin Med. 2025; 14 (14): 4849. https://doi.org/10.3390/jcm14144849. 22. Bendifallah S., Roman H., Suisse S., et al. Validation of a saliva micro-RNA signature for endometriosis. NEJM Evid. 2025; 4 (11): EVIDoa2400195. https://doi.org/10.1056/EVIDoa2400195. 23. Galliamov E.A., Unanyan A.L., Agapov M.A., et al. Deep infiltrative endometriosis of the rectovaginal septum involving the rectum. current state of the problem. Surgical Practice (Russia). 2019; 4: 18–31 (in Russ.). https://doi.org/10.38181/issn2223-2427.2019.4.18-31. 24. Gerges B., Li W., Leonardi M., Mol B.W., Condous G. Optimal imaging modality for detection of rectosigmoid deep endometriosis: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2021; 58 (2): 190–200. https://doi.org/10.1002/uog.23148. 25. Brunelli A.C., Brito L.G.O., Moro F.A.S., et al. Ultrasound elastography for the diagnosis of endometriosis and adenomyosis: a systematic review with meta-analysis. Ultrasound Med Biol. 2023; 49 (3): 699–709. https://doi.org/10.1016/j.ultrasmedbio.2022.11.006. 26. American College of Obstetricians & Gynecologists’ Committee on Clinical Practice Guidelines – Gynecology. Diagnosis of endometriosis. Obstet Gynecol. 2026; 147 (3): 432–48. https://doi.org/10.1097/AOG.0000000000006181. 27. Burgard C., Rosar F., Ezziddin S., et al. [68Ga]Ga FAPI-04 PET/CT in a patient with endometriosis: a potential game changer? Eur J Nucl Med Mol Imaging. 2025; 52 (12): 4350–1. https://doi.org/10.1007/s00259025-07252-9. 28. Thomassin-Naggara I., Dolciami M., Chamie L.P., et al. ESUR consensus MRI for endometriosis: protocol, lexicon, and compartmentbased analysis. Eur Radiol. 2025; 35: 7272–86. https://doi.org/10.1007/s00330-025-11611-3. 29. Hélage S., Laponche C., Homps M., et al. The Hôtel-Dieu MRI classification of uterosacral ligament involvement in endometriosis: a pictorial guide to clinical use. Diagnostics. 2025; 15 (12): 1508. https://doi.org/10.3390/diagnostics15121508. 30. Mohamed Y., Kol S.Q., Stoker J., Bipat S. Deep endometriosis: evaluation of ENZIAN and #ENZIAN classification systems by MRI compared with surgery – a meta-analysis. Eur Radiol. 2026; 36 (6): 4489–502. https://doi.org/10.1007/s00330-025-12154-3. 31. Moassefi M., Faghani S., Khosravi B., et al. Advancing endometriosis detection in daily practice: a deep learning-enhanced multi-sequence MRI analytical model. Abdom Radiol. 2026; 51 (1): 238–49. https://doi.org/10.1007/s00261-025-04942-8. 32. Figueredo W.K.R., Silva A.C., Paiva A.C., et al. Automatic segmentation of deep endometriosis in the rectosigmoid using deep learning. Image Vision Computing. 2024; 151 (1): 105261. https://doi.org/10.1016/j.imavis.2024.105261. 33. Becker C.M., Bokor A., Heikinheimo O., et al. ESHRE guideline: endometriosis. Hum Reprod Open. 2022; 2022 (2): hoac009. https://doi.org/10.1093/hropen/hoac009. 34. Vercellini P., Viganò P., Somigliana E., Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014; 10 (5): 261–75. https://doi.org/10.1038/nrendo.2013.255. 35. Adamyan L.V., Arslanyan K.N., Kharchenko E.I., Loginova O.N. Modern trends in the treatment of endometriosis. Russian Journal of Human Reproduction. 2019; 25 (6): 58–66 (in Russ.). https://doi.org/10.17116/repro20192506158. 36. Taylor H.S., Kotlyar A.M., Flores V.A. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. Lancet. 2021; 397 (10276): 839–52. https://doi.org/10.1016/S01406736(21)00389-5. 37. Roman H. A national snapshot of the surgical management of deep infiltrating endometriosis of the rectum and colon in France in 2015: a multicenter series of 1135 cases. J Gynecol Obstet Hum Reprod. 2017; 46 (2): 159–65. https://doi.org/10.1016/j.jogoh.2016.09.004. 38. Donnez J., Jadoul P., Colette S. et al. Deep rectovaginal endometriotic nodules: perioperative complications from a series of 3,298 patients operated on by the shaving technique. Gynecol Surg. 2013; 10 (1): 31–40. https://doi.org/10.1007/s10397-012-0759-z. 39. Chapron C., Marcellin L., Borghese B., Santulli P. Rethinking mechanisms, diagnosis and management of endometriosis. Nat Rev Endocrinol. 2019; 15 (11): 666–82. https://doi.org/10.1038/s41574-019-0245-z. 40. Adamyan L.V., Pivazyan L.G., Kurbatova K.S., et al. Oxidative stress, ferroptosis, somatic mutations, antioxidant therapy, and endometriosis: a new perspective on the issue. Russian Journal of Human Reproduction. 2024; 30 (6): 32–44 (in Russ.). https://doi.org/10.17116/repro20243006132. 41. Kłodnicka K., Michalska A., Januszewski J. From inflammation to malignancy: the link between endometriosis and gynecological cancers. Int J Mol Sci. 2025; 26 (24): 11816. https://doi.org/10.3390/ijms262411816. 42. Moustafa S., Burn M., Mamillapalli R., et al. Accurate diagnosis of endometriosis using serum microRNAs. Clin Chem. 2020; 66 (7): 911– 20. https://doi.org/10.1093/clinchem/hvaa124. 43. Qin X., Yan L., Zhao X., et al. microRNA-21 overexpression contributes to cell proliferation by targeting PTEN in endometrioid endometrial cancer. Oncol Lett. 2012; 4 (6): 1290–6. https://doi.org/10.3892/ol.2012.896. 44. Cheng Y., Guo Q., Cheng Y., et al. Endostatin-expressing endometrial mesenchymal stem cells inhibit angiogenesis in endometriosis through the miRNA-21-5p/TIMP3/PI3K/Akt/mTOR pathway. Stem Cells Transl Med. 2025; 14 (2): szae079. https://doi.org/10.1093/stcltm/szae079. 45. Carvalho M.J., Santos F., Vieira V., et al. Targeting endometrial stem cell in endometriosis treatment, a scoping review. J Gynecol Obstet Hum Reprod. 2026; 55 (4): 103123. https://doi.org/10.1016/j.jogoh.2026.103123. 46. Chen P., Mamillapalli R., Habata S., Taylor H.S. Endometriosis stromal cells induce bone marrow mesenchymal stem cell differentiation and PD-1 expression through paracrine signaling. Mol Cell Biochem. 2021; 476 (4): 1717–27. https://doi.org/10.1007/s11010020-04012-1. 47. Wang X., He J., Shen S., et al. The role of insulin-like growth factor binding proteins in TGF-β1-induced fibroblast-myofibroblast transition during endometriosis fibrosis. Cell Signal. 2026; 140: 112362. https://doi.org/10.1016/j.cellsig.2026.112362. 48. Palmer S.S., Altan M., Denis D., et al. Bentamapimod (JNK Inhibitor AS602801) induces regression of endometriotic lesions in animal models. Reprod Sci. 2016; 23 (1): 11–23. https://doi.org/10.1177/1933719115600553. 49. Ganieva U., Nakamura T., Osuka S., et al. Involvement of transcription factor 21 in the pathogenesis of fibrosis in endometriosis. Am J Pathol. 2020; 190 (1): 145–57. https://doi.org/10.1016/j.ajpath.2019.09.008. 50. Tsitskarava D.Z., Yarmolinskaya M.I., Selkov S.A. Efficacy of cytokine therapy in the combined treatment of patients with deep infiltrating endometriosis. Journal of Obstetrics and Women's Diseases. 2016; 65 (S): 66–8 (in Russ.). 51. El-Zayadi A.A., Mohamed S.A., Arafa M., et al. Anti-IL-6 receptor monoclonal antibody as a new treatment of endometriosis. Immunol Res. 2020; 68 (6): 389–97. https://doi.org/10.1007/s12026-020-09153-5. 52. Lisovskaya E.V., Khilkevich E.G., Chuprynin V.D., et al. Enhanced recovery after surgery protocols in patients with deep infiltrating colorectal endometriosis. Akusherstvo i ginekologiya / Obstetrics and Gynecology. 2019; 1: 34–41 (in Russ.). https://doi.org/10.18565/aig.2019.1.34-41. 53. Nelson G., Bakkum-Gamez J., Kalogera E., et al. Guidelines for perioperative care in gynecologic/oncology: Enhanced Recovery After Surgery (ERAS) Society recommendations – 2019 update. Int J Gynecol Cancer. 2019; 29 (4): 651–68. https://doi.org/10.1136/ijgc-2019-000356. 54. Muzii L., Di Tucci C., Galati G., et al. The efficacy of dienogest in reducing disease and pain recurrence after endometriosis surgery: a systematic review and meta-analysis. Reprod Sci. 2023; 30 (11): 3135–43. https://doi.org/10.1007/s43032-023-01266-0. 55. Del Forno S., Arena A., Pellizzone V., et al. Assessment of levator hiatal area using 3D/4D transperineal ultrasound in women with deep infiltrating endometriosis and superficial dyspareunia treated with pelvic floor muscle physiotherapy: randomized controlled trial. Ultrasound Obstet Gynecol. 2021; 57 (5): 726–32. https://doi.org/10.1002/uog.23590. 56. Del Forno S., Cocchi L., Arena A., et al. Effects of pelvic floor muscle physiotherapy on urinary, bowel, and sexual functions in women with deep infiltrating endometriosis: a randomized controlled trial. Medicina. 2023; 60 (1): 67. https://doi.org/10.3390/medicina60010067. 57. Wójcik M., Szczepaniak R., Placek K. Physiotherapy management in endometriosis. Int J Environ Res Public Health. 2022; 19 (23): 16148. https://doi.org/10.3390/ijerph192316148. 58. Zegrea A., Ojala E., Suvitie P., et al. Sacral neuromodulation in endometriosis – a promising treatment option for chronic pelvic pain. Acta Obstet Gynecol Scand. 2023; 102 (12): 1634–42. https://doi.org/10.1111/aogs.14690. 59. da Silva Freitas T., Barbosa de Oliveira A.J., Golovac S., Assumpcao de Monaco B. Dorsal root ganglion stimulation for chronic pelvic pain secondary to endometriosis. Neuromodulation. 2025; 28 (5): 825–31. https://doi.org/10.1016/j.neurom.2024.11.007. 60. Mechsner S., Grünert J., Wiese J.J., et al. Transcranial direct current stimulation to reduce chronic pelvic pain in endometriosis: phase II randomized controlled clinical trial. Pain Med. 2023; 24 (7): 809–17. https://doi.org/10.1093/pm/pnad031. 61. Dubernard G., Maissiat E., Legendre G., et al. Evaluating the safety of high-intensity focused ultrasound treatment for rectal endometrio- sis: results from a French prospective multicentre study including 60 patients. Hum Reprod. 2024; 39 (8): 1673–83. https://doi.org/10.1093/humrep/deae127. 62. Abulughod N., Valakas S., El-Assaad F. Dietary and nutritional interventions for the management of endometriosis. Nutrients. 2024; 16 (23): 3988. https://doi.org/10.3390/nu16233988. 63. Kalopedis E.A., Zorgani A., Zinovkin D.A., et al. Leveraging the role of the microbiome in endometriosis: novel non-invasive and therapeutic approaches. Front Immunol. 2025; 16: 1631522. https://doi.org/10.3389/fimmu.2025.1631522. 64. Qiao L., Zhao D., Wu J. Evaluation of microecological therapy in endometriosis through modulation of the gut microbiota. Eur J Med Res. 2025; 30: 1084. https://doi.org/10.1186/s40001-025-03334-4. 65. Melkozerova O.A., Braslavskaya E.P., Mikhelson A.A., et al. The role of the intestinal and reproductive tract microbiota in the progression and recurrence of genital endometriosis. Russian Journal of Human Reproduction. 2023; 29 (4): 68–74 (in Russ.). https://doi.org/10.17116/repro20232904168. 66. Hansen K.E., Brandsborg B., Kesmodel U.S., et al. Psychological interventions improve quality of life despite persistent pain in endometriosis: results of a 3-armed randomized controlled trial. Qual Life Res. 2023; 32 (6): 1727–44. https://doi.org/10.1007/s11136-02303346-9. 67. Samami E., Shahhosseini Z., Khani S., Elyasi F. Pain-focused psychological interventions in women with endometriosis: a systematic review. Neuropsychopharmacol Rep. 2023; 43 (3): 310–9. https://doi.org/10.1002/npr2.12348. 68. Mardon A.K., Leake H.B., Hayles C., et al. The efficacy of selfmanagement strategies for females with endometriosis: a systematic review. Reprod Sci. 2023; 30 (2): 390–407. https://doi.org/10.1007/s43032-022-00952-9. Review For citations: Khlopkova S.V., Shatilina A.Yu., Martirosyan N.A., Khadanovich M.R., Lazareva K.V., Grigoryeva K.N., Khizroeva J.Kh., Solopova A.G. Looking ahead: new approaches to the diagnosis, treatment, and rehabilitation of patients with deep infiltrating endometriosis. FARMAKOEKONOMIKA. Modern Pharmacoeconomics and Pharmacoepidemiology. 2026;19(3):617–626. (In Russ.) https://doi.org/10.17749/2070-4909/farmakoekonomika.2026.401 JATS XML This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.