• Ioana PAVALEANU “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • Raluca Anca BALAN “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • Adriana GRIGORAS “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • Teodora Ana BALAN “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • L. V. BOICULESE “Grigore T. Popa” University of Medicine and Pharmacy Iasi
  • Cornelia AMALINEI “Grigore T. Popa” University of Medicine and Pharmacy Iasi


Aim: Endometriosis, a chronic estrogen-dependent disease, is associated with persistent pelvic pain and is classified as a neuro-inflammatory disorder. This study aimed to decipher the inflammatory milieu in endometriosis, focusing on the lymphoid infiltrate represented by the CD4+ cells, CD8+ cells, and CD68+ macrophages, and the possible correlation with steroid hormone receptor expressions. Material and methods: Research conducted at the “Elena Doamna” Clinical Hospital and the “Grigore T. Popa” University of Medicine and Pharmacy in Iași, Romania, involved retrospective analysis of 53 patients with endometriosis from 2018 to 2023. Results: Through immunohistochemical assays, we observed correlations between CD4 and CD8 expressions, and between CD4, CD68, and the PR score. Also, a possible causality between the macrophage infiltrate and PR expression could be suggested. Conclusions: The inflammatory infiltrate’s analysis in endometriosis provides a deeper knowledge of its pathological development and the interplay of inflammatory cells. Understanding these receptors might guide future treatment strategies for better disease management.

Author Biographies

Ioana PAVALEANU, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Faculty of Medicine
Department of Mother and Child Medicine

Raluca Anca BALAN, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Faculty of Medicine
Department of Morpho-functional Sciences (I),

Adriana GRIGORAS, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Faculty of Medicine
Department of Morpho-functional Sciences (I)
Institute of Legal Medicine, Iaşi, Romania
Department of Histopathology

Teodora Ana BALAN, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Faculty of Medicine
Department of Morpho-functional Sciences (I)

L. V. BOICULESE, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Faculty of Medicine
Department of Preventive Medicine and Interdisciplinarity

Cornelia AMALINEI, “Grigore T. Popa” University of Medicine and Pharmacy Iasi

Faculty of Medicine
Department of Morpho-functional Sciences (I)
Institute of Legal Medicine, Iaşi, Romania
Department of Histopathology


1. Zondervan KT, Becker CM, Missmer SA. Endometriosis. N Engl J Med 2020; 382(13): 1244-1256.
2. Saunders PTK, Horne AW. Endometriosis: Etiology, pathobiology, and therapeutic prospects. Cell 2021; 184: 2807-2824.
3. Bourdon M, Santulli P, Jeljeli M, et al. Immunological changes associated with adenomyosis: a sys-tematic review. Hum Reprod Update 2021; 27(1): 108-129.
4. Păvăleanu I, Lozneanu L, Balan RA, Giuşcă SE, Avădănei ER, Căruntu ID, et al. Insights into mo-lecular pathways of endometriosis and endometriosis-related ovarian carcinoma. Rom J Morphol Em-bryol 2020; 61(3): 739-749.
5. Shen HH, Zhang T, Yang HL, et al. Ovarian hormones-autophagy-immunity axis in menstruation and endometriosis. Theranostics 2021; 11(7): 3512-3526.
6. Kisovar A, Becker CM, Granne I, Southcombe J. The role of CD8+ T cells in endometriosis: a sys-tematic review. Front Immunol 2023; 14: 1225639.
7. Yang Z, Kong B, Mosser DM, Zhang X. TLRs, macrophages, and NK cells: our understandings of their functions in uterus and ovary. Int Immunopharmacol 2011; 11: 1442-1450.
8. Nie J, Liu X. Immunoreactivity of CD68, granulocyte-macrophage colony-stimulating factors receptor and vonwillebrand factor and its association with dysmenorrhea severity and the amount of menses in adenomyosis. Int J Clin Exp Med 2016; 9: 20856-20865.
9. Nie MF, Xie Q, Wu YH, et al. Serum and ectopic endometrium from women with endometriosis modulate macrophage M1/M2 polarization via the Smad2/Smad3 pathway. J Immunol Res 2018; 2018: 6285813.
10. García-Gómez E, Vázquez-Martínez ER, Reyes-Mayoral C, Cruz-Orozco OP, Camacho-Arroyo I, Cerbón M. Regulation of inflammation pathways and inflammasome by sex steroid hormones in endo-metriosis. Front Endocrinol (Lausanne) 2019; 10: 935.
11. Amalinei C, Păvăleanu I, Lozneanu L, Balan R, Giuşcă SE, Căruntu ID. Endometriosis - insights into a multifaceted entity. Folia Histochem Cytobiol 2018; 56(2): 61-82.
12. Raonic J, Lopicic M, Vuckovic L, Vucinic J. Immunohistochemical analysis of CD68, CD4, CD8 and CD20 expression in cervical dysplasia and its relationship with HR-HPV infection. Eur Rev Med Pharmacol Sci 2021; 25(23): 7598-7606.
13. Sethi S, Sarkar FH, Ahmed Q, et al. Molecular markers of epithelial-to-mesenchymal transition are associated with tumor aggressiveness in breast carcinoma. Transl Oncol 2011; 4(4): 222-226.
14. Matsumoto T, Yamazaki M, Takahashi H, et al. Distinct β-catenin and PIK3CA mutation profiles in endometriosis-associated ovarian endometrioid and clear cell carcinomas. Am J Clin Pathol 2015; 144(3): 452-463.
15. Allred DC, Harvey JM, Berardo M, Clark GM. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 1998; 11(2): 155-168.
16. Anton SC, Nicolaiciuc D, Costachescu G, et al. The histopathological and immuno-histochemical profile of malignant breast tumors in North-East Romania. Med Surg J 2023; 127(1): 32-42 / doi: 10.22551/revmedchir.v127i1.
17. Alexa-Stratulat T, Neagu M, Neagu AI, Alexa ID, Ioan BG. Consent for participating in clinical trials - Is it really informed? Dev World Bioeth 2018; 18(3): 299-306.
18. Mooji JM, Peters J, Janzing D, Zscheischler J, Schoelkopf B. Distinguishing Cause from Effect Using Observational Data: Methods and Benchmarks. Journal of Machine Learning Research 2016; 17: 1-102.
19. Peters J, Janzing D, Schoelkopf B. Elements of Causal Interference - Foundation and Learning Algo-rithms. MIT Press 2017.
20. Sahraei SS, Kowsari A, Asl FD, Sheykhhasan M, Naserpoor L, Sheikholeslami A. Evaluating the effect of conditioned medium from endometrial stem cells on endometriosis-derived endometrial stem cells. Anat Cell Biol 2022; 55(1): 100-108.
21. Halme J, Becker S, Haskill S. Altered maturation and function of peritoneal macrophages: possible role in the pathogenesis of endometriosis. Am J Obstet Gynecol 1987; 156(4): 783-789.
22. Lloyd AF, Miron VE. Cellular and molecular mechanisms underpinning macrophage activation during remyelination. Front Cell Dev Biol 2016; 4: 60 / doi: 10.3389/fcell.2016.00060.
23. Olkowska-Truchanowicz J, Bocian K, Maksym RB, Białoszewska A, Włodarczyk D, Baranowski W, et al. CD4+ CD25+ FOXP3+ regulatory T cells in peripheral blood and peritoneal fluid of patients with endometriosis. Hum Reprod, 2013; 28(1):119–124. des346 PMID: 23019301
24. Abramiuk M, Grywalska E, Małkowska P, Sierawska O, Hrynkiewicz R, Niedźwiedzka-Rystwej P. The Role of the Immune System in the Development of Endometriosis. Cells 2022; 11(13): 2028 / doi: 10.3390/cells11132028
25. Lee SK, Kim CJ, Kim DJ, Kang JH. Immune cells in the female reproductive tract. Immune Netw 2015; 15(1): 16-26.
26. Szukiewicz D. Epigenetic regulation and T-cell responses in endometriosis - something other than autoimmunity. Front Immunol 2022; 13: 943839.
27. Yu K, Huang ZY, Xu XL, Li J, Fu XW, Deng SL. Estrogen receptor function: impact on the human endometrium. Front Endocrinol (Lausanne) 2022; 13: 827724.
28. Guo M, Bafligil C, Tapmeier T, et al. Mass cytometry analysis reveals a distinct immune environment in peritoneal fluid in endometriosis: a characterization study. BMC Med 2020; 18(1): 3 / doi: 10.1186/s12916-019-1470-y.
29. Slabe N, Meden-Vrtovec H, Verdenik I, Kosir-Pogacnik R, Ihan A. Cytotoxic T-cells in peripheral blood in women with endometriosis. Geburtshilfe Frauenheilkd 2013; 73(10): 1042-1048.
30. Vargas E, Garcıa-Moreno E, Aghajanova L, et al. The mid-secretory endometrial transcriptomic landscape in endometriosis: a meta-analysis. Hum Reprod Open 2022; 2022(2): hoac016.
31. Khan KN, Kitajima M, Hiraki K, et al. Immunopathogenesis of Pelvic Endometriosis: Role of Hepatocyte Growth Factor, Macrophages and Ovarian Steroids. Am J Reprod Immunol 2008; 60: 383-404.
32. Zhang P, Wang, G. Progesterone resistance in endometriosis: Current evidence and putative mecha-nisms. Int J Mol Sci 2023; 24: 6992.
33. Chantalat E, Valera MC, Vaysse C, et al. Estrogen receptors and endometriosis. Int J Mol Sci 2020; 21(8): 2815.
34. Hogg C, Horne AW, Greaves E. Endometriosis-Associated Macrophages: Origin, Phenotype, and Function. Front Endocrinol (Lausanne) 2020; 11: 7 / doi: 10.3389/fendo.2020.00007.
35. Pepe G, Braga D, Renzi TA, et al. Self-renewal and phenotypic conversion are the main physiological responses of macrophages to the endogenous estrogen surge. Sci Rep 2017; 7: 44270.
36. Stewart JA, Bulmer JN, Murdoch AP. Endometrial leucocytes: expression of steroid hormone recep-tors. J Clin Pathol 1998; 51: 121-126.
37. Cheng CW, Bielby H, Licence D, Smith SK, Print CG, Charnock-Jones DS. Quantitative cellular and molecular analysis of the effect of progesterone withdrawal in a murine model of decidualization. Biol Reprod 2007; 76: 871-883.
38. Poorasamy J, Patil JSA Ghosh D. Progesterone Resistance in Endometriosis. EMJ Reprod Health 2022; 8(1): 51-63.