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Diagnostic accuracy of interleukin-6 levels in peritoneal fluid for detection of endometriosis

  • General Gynecology
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

To determine, with extended receiver operating characteristic (ROC) curve analysis, the diagnostic value of cytokines showing significantly different peritoneal concentrations between women with and without endometriosis.

Methods

Multiplex cytokine concentration measurement of IL-2, IL-4, IL-6, IL-10, TNF-α and IFN-γ levels in peritoneal fluid of women with minimal to mild (n = 10) and moderate to severe (n = 26) endometriosis, and 42 controls.

Results

Only IL-6 and IL-10 concentrations were significantly higher in endometriosis patients than in controls. Specifically, significantly higher IL-6 and IL-10 levels were found in moderate to severe but not in minimal to mild endometriosis as compared to controls. For evaluation of diagnostic significance, ROC analysis determined discriminating parameters for IL-6, while those calculated for IL-10 were useless. Importantly, ROC analysis for IL-6 levels limited to women with moderate to severe endometriosis showed the highest area under the curve with the sample size sufficient to achieve 90 % power of the test. Finally, extended ROC including cost of analysis for this group of patients determined the optimal cut-off leading to high specificity and positive likelihood ratio resulting in 79 % effectiveness of the test.

Conclusions

While our outcomes show moderate usefulness of peritoneal IL-6 levels in discrimination of moderate to severe endometriosis, further studies might be needed to determine the usefulness of peritoneal IL-6 levels in detection of early stages of endometriosis, as such a finding would be more relevant in clinical decision making.

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References

  1. Hsu AL, Khachikyan I, Stratton P (2010) Invasive and noninvasive methods for the diagnosis of endometriosis. Clin Obstet Gynecol 53:413–419

    Article  PubMed  Google Scholar 

  2. Bulun SE (2009) Endometriosis. N Engl J Med 360:268–279

    Article  PubMed  CAS  Google Scholar 

  3. Asante A, Taylor RN (2011) Endometriosis: the role of neuroangiogenesis. Annu Rev Physiol 73:163–182

    Article  PubMed  CAS  Google Scholar 

  4. Eskenazi B, Warner M, Bonsignore L, Olive D, Samuels S, Vercellini P (2001) Validation study of nonsurgical diagnosis of endometriosis. Fertil Steril 76:929–935

    Article  PubMed  CAS  Google Scholar 

  5. Bazot M, Lafont C, Rouzier R, Roseau G, Thomassin-Naggara I, Daraï E (2009) Diagnostic accuracy of physical examination, transvaginal sonography, rectal endoscopic sonography, and magnetic resonance imaging to diagnose deep infiltrating endometriosis. Fertil Steril 92:1825–1833

    Article  PubMed  Google Scholar 

  6. Bedaiwy MA, Falcone T (2004) Laboratory testing for endometriosis. Clin Chim Acta 340:41–56

    Article  PubMed  CAS  Google Scholar 

  7. Whiteside TL (1994) Cytokine measurements and interpretation of cytokine assays in human disease. J Clin Immunol 14:327–339

    Article  PubMed  CAS  Google Scholar 

  8. Wu MY, Ho HN (2003) The role of cytokines in endometriosis. Am J Reprod Immunol 49:285–296

    Article  PubMed  Google Scholar 

  9. Gazvani R, Templeton A (2002) Peritoneal environment, cytokines and angiogenesis in the pathophysiology of endometriosis. Reproduction 123:217–226

    Article  PubMed  CAS  Google Scholar 

  10. Kyama CM, Debrock S, Mwenda JM, D’Hooghe TM (2003) Potential involvement of the immune system in the development of endometriosis. Reprod Biol Endocrinol 1:123

    Article  PubMed  Google Scholar 

  11. Berkkanoglu M, Arici A (2003) Immunology and endometriosis. Am J Reprod Immunol 50:48–59

    Article  PubMed  Google Scholar 

  12. Kirchhoff D, Kaulfuss S, Fuhrmann U, Maurer M, Zollner TM (2012) Mast cells in endometriosis: guilty or innocent bystanders? Expert Opin Ther Targets 16:237–241

    Article  PubMed  CAS  Google Scholar 

  13. Bedaiwy MA, Falcone T, Sharma RK, Goldberg JM, Attaran M, Nelson DR, Agarwal A (2002) Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum Reprod 17:426–431

    Article  PubMed  CAS  Google Scholar 

  14. Drosdzol-Cop A, Skrzypulec-Plinta V (2012) Selected cytokines and glycodelin A levels in serum and peritoneal fluid in girls with endometriosis. J Obstet Gynaecol Res 38:1245–1253

    Article  PubMed  CAS  Google Scholar 

  15. Drosdzol-Cop A, Skrzypulec-Plinta V, Stojko R (2012) Serum and peritoneal fluid immunological markers in adolescent girls with chronic pelvic pain. Obstet Gynecol Surv 67:374–381

    Article  PubMed  Google Scholar 

  16. Mihalyi A, Gevaert O, Kyama CM, Simsa P, Pochet N, De Smet F, De Moor B, Meuleman C, Billen J, Blanckaert N, Vodolazkaia A, Fulop V, D’Hooghe TM (2010) Non-invasive diagnosis of endometriosis based on a combined analysis of six plasma biomarkers. Hum Reprod 25:654–664

    Article  PubMed  CAS  Google Scholar 

  17. Vodolazkaia A, El-Aalamat Y, Popovic D, Mihalyi A, Bossuyt X, Kyama CM, Fassbender A, Bokor A, Schols D, Huskens D, Meuleman C, Peeraer K, Tomassetti C, Gevaert O, Waelkens E, Kasran A, De Moor B, D’Hooghe TM (2012) Evaluation of a panel of 28 biomarkers for the non-invasive diagnosis of endometriosis. Hum Reprod 27:2698–2711

    Article  PubMed  CAS  Google Scholar 

  18. Seeber B, Sammel MD, Fan X, Gerton GL, Shaunik A, Chittams J, Barnhart KT (2008) Panel of markers can accurately predict endometriosis in a subset of patients. Fertil Steril 89:1073–1081

    Article  PubMed  CAS  Google Scholar 

  19. Agic A, Djalali S, Wolfler MM, Halis G, Diedrich K, Hornung D (2008) Combination of CCR1 mRNA, MCP1, and CA125 measurements in peripheral blood as a diagnostic test for endometriosis. Reprod Sci 15:906–911

    Article  PubMed  Google Scholar 

  20. D’Hooghe TM, Mihalyi AM, Simsa P, Kyama CK, Peeraer K, De Loecker P, Meeuwis L, Segal L, Meuleman C (2006) Why we need a noninvasive diagnostic test for minimal to mild endometriosis with a high sensitivity. Gynecol Obstet Invest 62:136–138

    Article  PubMed  Google Scholar 

  21. Barcz E, Milewski L, Dziunycz P, Kamiński P, Płoski R, Malejczyk J (2012) Peritoneal cytokines and adhesion formation in endometriosis: an inverse association with vascular endothelial growth factor concentration. Fertil Steril 97:1380–1386

    Article  PubMed  CAS  Google Scholar 

  22. Podgaec S, Abrao MS, Dias JA, Rizzo LV, de Oliveira RM, Baracat EC (2007) Endometriosis: an inflammatory disease with a Th2 immune response component. Hum Reprod 22:1373–1379

    Article  PubMed  CAS  Google Scholar 

  23. Mier-Cabrera J, Jiménez-Zamudio L, García-Latorre E, Cruz-Orozco O, Hernández-Guerrero C (2011) Quantitative and qualitative peritoneal immune profiles, T-cell apoptosis and oxidative stress-associated characteristics in women with minimal and mild endometriosis. BJOG 118:6–16

    Article  PubMed  CAS  Google Scholar 

  24. Revised American Society for Reproductive Medicine classification of endometriosis: 1996 (1997) Fertil Steril 67:817–821

    Article  Google Scholar 

  25. Gmyrek GB, Sozanski R, Jerzak M, Chrobak A, Wickiewicz D, Skupnik A, Sieradzka U, Fortuna W, Gabrys M, Chelmonska-Soyta A (2005) Evaluation of monocyte chemotactic protein-1 levels in peripheral blood of infertile women with endometriosis. Eur J Obstet Gynecol Reprod Biol 122:199–205

    Article  PubMed  CAS  Google Scholar 

  26. Morgan E, Varro R, Sepulveda H, Ember JA, Apgar J, Wilson J, Lowe L, Chen R, Shivraj L, Agadir A, Campos R, Ernst D, Gaur A (2004) Cytometric bead array: a multiplexed assay platform with applications in various areas of biology. Clin Immunol 110:252–266

    Article  PubMed  CAS  Google Scholar 

  27. Akobeng AK (2007) Understanding diagnostic tests 3: receiver operating characteristic curves. Acta Paediatr 96:644–647

    Article  PubMed  Google Scholar 

  28. Henderson AR (2005) The bootstrap: a technique for data-driven statistics. Using computer-intensive analyses to explore experimental data. Clin Chim Acta 359:1–26

    Article  PubMed  CAS  Google Scholar 

  29. Zweig MH, Campbell G (1993) Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 39:561–577

    PubMed  CAS  Google Scholar 

  30. Efron B, Tibshirani RJ (1993) An introduction to the Bootstrap. Chapman & Hall/CRC, New York

    Google Scholar 

  31. Youden WJ (1950) Index for rating diagnostic tests. Cancer 3:32–35

    Article  PubMed  CAS  Google Scholar 

  32. Glas AS, Lijmer JG, Prins MH, Bonsel GJ, Bossuyt PM (2003) The diagnostic odds ratio: a single indicator of test performance. J Clin Epidemiol 56:1129–1135

    Article  PubMed  Google Scholar 

  33. Harada T, Enatsu A, Mitsunari M, Nagano Y, Ito M, Tsudo T, Taniguchi F, Iwabe T, Tanikawa M, Terakawa N (1999) Role of cytokines in progression of endometriosis. Gynecol Obstet Invest 47(suppl 1):34–40

    Article  PubMed  CAS  Google Scholar 

  34. OuYang Z, Hirota Y, Osuga Y, Hamasaki K, Hasegawa A, Tajima T, Hirata T, Koga K, Yoshino O, Harada M, Takemura Y, Nose E, Yano T, Taketani Y (2008) Interleukin-4 stimulates proliferation of endometriotic stromal cells. Am J Pathol 173:463–469

    Article  PubMed  CAS  Google Scholar 

  35. Ho HN, Wu MY, Chao KH, Chen CD, Chen SU, Chen HF, Yang YS (1996) Decrease in interferon gamma production and impairment of T-lymphocyte proliferation in peritoneal fluid of women with endometriosis. Am J Obstet Gynecol 175:1236–1241

    Article  PubMed  CAS  Google Scholar 

  36. Tabibzadeh S, Becker JL, Parsons AK (2003) Endometriosis is associated with alterations in the relative abundance of proteins and IL-10 in the peritoneal fluid. Front Biosci 8:a70–a78

    Article  PubMed  CAS  Google Scholar 

  37. Milewski Ł, Barcz E, Dziunycz P, Radomski D, Kamiński P, Roszkowski PI, Korczak-Kowalska G, Malejczyk J (2008) Association of leptin with inflammatory cytokines and lymphocyte subpopulations in peritoneal fluid of patients with endometriosis. J Reprod Immunol 79:111–117

    Article  PubMed  CAS  Google Scholar 

  38. Milewski Ł, Dziunycz P, Barcz E, Radomski D, Roszkowski PI, Korczak-Kowalska G, Kamiński P, Malejczyk J (2011) Increased levels of human neutrophil peptides 1, 2, and 3 in peritoneal fluid of patients with endometriosis: association with neutrophils, T cells and IL-8. J Reprod Immunol 91:64–70

    Article  PubMed  CAS  Google Scholar 

  39. Seeber BE, Barnhart KT (2012) Diagnosis of endometriosis. Biomarkers. In: Giudice LC, Evers JLH, Healy DL (eds) Endometriosis: science and practice. Wiley, London, pp 309–323

    Chapter  Google Scholar 

  40. Perkins NJ, Schisterman EF (2006) The inconsistency of “optimal” cutpoints obtained using two criteria based on the receiver operating characteristic curve. Am J Epidemiol 163:670–675

    Article  PubMed  Google Scholar 

  41. Irwin RJ, Irwin TC (2011) A principled approach to setting optimal diagnostic thresholds: where ROC and indifference curves meet. Eur J Intern Med 22:230–234

    Article  PubMed  Google Scholar 

  42. Sasse EA (2002) Objective evaluation of data in screening for disease. Clin Chim Acta 315:17–30

    Article  PubMed  CAS  Google Scholar 

  43. Khan KN, Masuzaki H, Fujishita A, Kitajima M, Sekine I, Ishimaru T (2004) Higher activity by opaque endometriotic lesions than nonopaque lesions. Acta Obstet Gynecol Scand 83:375–382

    PubMed  Google Scholar 

  44. Lawson C, Al-Akoum M, Maheux R, Akoum A (2007) Increased expression of interleukin-1 receptor type 1 in active endometriotic lesions. Reproduction 133:265–274

    Article  PubMed  CAS  Google Scholar 

  45. Hudelist G, Oberwinkler KH, Singer CF, Tuttlies F, Rauter G, Ritter O, Keckstein J (2009) Combination of transvaginal sonography and clinical examination for preoperative diagnosis of pelvic endometriosis. Hum Reprod 24:1018–1024

    Article  PubMed  CAS  Google Scholar 

  46. Elshal MF, McCoy JP (2006) Multiplex bead array assays: performance evaluation and comparison of sensitivity to ELISA. Methods 38:317–323

    Article  PubMed  CAS  Google Scholar 

  47. Moncunill G, Aponte JJ, Nhabomba AJ, Dobaño C (2013) Performance of multiplex commercial kits to quantify cytokine and chemokine responses in culture supernatants from Plasmodium Falciparum stimulations. PLoS One 8:e52587

    Article  PubMed  CAS  Google Scholar 

  48. Van Belle VM, Van Calster B, Timmerman D, Bourne T, Bottomley C, Valentin L, Neven P, Van Huffel S, Suykens JA, Boyd S (2012) A mathematical model for interpretable clinical decision support with applications in gynecology. PLoS One 7:e34312

    Article  PubMed  Google Scholar 

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Acknowledgments

This work was supported by Polish Ministry of Science and Higher Education grant nos. N40701132/0313 (to A.C.), and 2P05E 02929 (to M.G.).

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We declare that we have no conflict of interest.

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Correspondence to Grzegorz B. Gmyrek.

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Wickiewicz, D., Chrobak, A., Gmyrek, G.B. et al. Diagnostic accuracy of interleukin-6 levels in peritoneal fluid for detection of endometriosis. Arch Gynecol Obstet 288, 805–814 (2013). https://doi.org/10.1007/s00404-013-2828-6

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  • DOI: https://doi.org/10.1007/s00404-013-2828-6

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