Interleukin-6 as A Useful Predictor of Endometriosis-Associated Infertility: A Systematic Review

Document Type : Systematic Review


1 Department of General Surgery and Medical Surgical Specialties, University of Catania, Catania, Italy

2 Department of Obstetrics and Gynaecology, Azienda di Rilievo Nazionale e di Alta Specializzazione (ARNAS) Garibaldi Nesima, Catania, Italy

3 Unit of Medical Statistics and Molecular Epidemiology, University Campus Bio-Medico of Rome, Rome, Italy

4 Department of Drug and Health Sciences, University of Catania, Catania, Italy


Endometriosis is a chronic inflammatory disease defined by the presence of endometrial-like tissue outside the
uterine cavity. Several authors have reported on the association between changes in inflammatory marker levels
and the maintenance or progression of endometriosis and associated infertility. Interleukin-6 (IL-6) is the most
studied cytokine in endometriosis and has important functions in reproductive physiology. The aim of this study is
to review systematically available evidence about altered IL-6 concentrations in endometriosis-related infertility.
This is a systematic review including all studies until December 2022 in which IL-6 in serum, peritoneal fluid,
follicular fluid, or endometrial biopsy specimens was measured and that correlated their findings with endometriosis-
associated infertility. Fifteen studies were included in the systematic review. There seems to be a correlation
between elevated serum and peritoneal fluid IL-6 concentrations and the occurrence of endometriosis-associated
infertility. IL-6 may be a potential diagnostic or biomarker tool for the prediction of endometriosis-related infertility.
However, the numerous biases affecting the available studies, and challenges in endometriosis research reproducibility
must be considered. Future investigations should pay attention to factors that may affect the results, such
as the choice of suitable control groups, and carefully consider other pathological conditions affecting the patients,
endometriosis stage, and type of lesion.


Main Subjects

  1. Bulun SE, Yilmaz BD, Sison C, Miyazaki K, Bernardi L, Liu S, et al. Endometriosis. Endocr Rev. 2019; 40(4): 1048-1079.

2 Newmark AL, Luciano DE, Ulrich A, Luciano AA. Medical manage­ment of endometriosis. Minerva Obstet Gynecol. 2021; 73(5): 572- 587.

  1. Agarwal SK, Chapron C, Giudice LC, Laufer MR, Leyland N, Miss­mer SA, et al. Clinical diagnosis of endometriosis: a call to action. Am J Obstet Gynecol. 2019; 220(4): 354.e1-354.e12.
  2. Malvezzi H, Hernandes C, Piccinato CA, Podgaec S. Interleukin in endometriosis-associated infertility-pelvic pain: systematic review and meta-analysis. Reproduction. 2019; 158(1): 1-12.
  3. Al-Jefout M. Laparoscopy for diagnosis and treatment of endome­triosis. In: Darwish A, editor. Advanced gynecologic endoscopy. IntechOpen, 2011.
  4. Jiang L, Yan Y, Liu Z, Wang Y. Inflammation and endometriosis. Front Biosci (Landmark Ed). 2016; 21(5): 941-948.
  5. Li C, Zhao HL, Li YJ, Zhang YY, Liu HY, Feng FZ, et al. The expres­sion and significance of leukemia inhibitory factor, interleukin-6 and vascular endothelial growth factor in Chinese patients with endome­triosis. Arch Gynecol Obstet. 2021; 304(1): 163-170.
  6. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mul­row CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021; 372: n71.
  7. Buyalos RP, Watson JM, Martinez-Maza O. Detection of interleukin-6 in human follicular fluid. Fertil Steril. 1992; 57(6): 1230-1234.
  8. Harada T, Yoshioka H, Yoshida S, Iwabe T, Onohara Y, Tanikawa M, et al. Increased interleukin-6 levels in peritoneal fluid of infertile pa­tients with active endometriosis. Am J Obstet Gynecol. 1997; 176(3): 593-597.
  9. Iwabe T, Harada T, Terakawa N. Role of cytokines in endometriosis-associated infertility. Gynecol Obstet Invest. 2002; 53 Suppl 1: 19- 25.
  10. Jørgensen H, Fedorcsak P, Isaacson K, Tevonian E, Xiao A, Beste M, et al. Endometrial cytokines in patients with and without endome­triosis evaluated for infertility. Fertil Steril. 2022; 117(3): 629-640.
  11. Kalu E, Sumar N, Giannopoulos T, Patel P, Croucher C, Sherriff E, et al. Cytokine profiles in serum and peritoneal fluid from infertile wom­en with and without endometriosis. J Obstet Gynaecol Res. 2007; 33(4): 490-495.
  12. Liu Y, Luo L, Zhao H. Changes of cytokines levels in peritoneal fluids of patients with endometriosis and its effect on reproductive activity. J Tongji Med Univ. 2000; 20(2): 163-165.
  13. Moberg C, Bourlev V, Ilyasova N, Olovsson M. Endometrial expres­sion of LIF and its receptor and peritoneal fluid levels of IL-1α and IL-6 in women with endometriosis are associated with the probability of pregnancy. Arch Gynecol Obstet. 2015; 292(2): 429-437.
  14. Pellicer A, Albert C, Mercader A, Bonilla-Musoles F, Remohí J, Simón C. The follicular and endocrine environment in women with endometriosis: local and systemic cytokine production. Fertil Steril. 1998; 70(3): 425-431.
  15. Singh AK, Dutta M, Chattopadhyay R, Chakravarty B, Chaudhury K. Intrafollicular interleukin-8, interleukin-12, and adrenomedullin are the promising prognostic markers of oocyte and embryo quality in women with endometriosis. J Assist Reprod Genet. 2016; 33(10): 1363-1372.
  16. Skrzypczak J, SzczepaƄska M, Puk E, Kamieniczna M, Kurpisz M. Peritoneal fluid cytokines and sICAM-1 in minimal endometriosis: search for discriminating factors between infertility and/or endome­triosis. Eur J Obstet Gynecol Reprod Biol. 2005; 122(1): 95-103.
  17. Wu G, Bersinger NA, Mueller MD, von Wolff M. Intrafollicular in­flammatory cytokines but not steroid hormone concentrations are increased in naturally matured follicles of women with proven endo­metriosis. J Assist Reprod Genet. 2017; 34(3): 357-364.
  18. Wunder DM, Mueller MD, Birkhäuser MH, Bersinger NA. Increased ENA-78 in the follicular fluid of patients with endometriosis. Acta Ob­stet Gynecol Scand. 2006; 85(3): 336-342.
  19. Gica N, Panaitescu AM, Iancu G, Botezatu R, Peltecu G, Gica C. The role of biological markers in predicting infertility associated with non-obstructive endometriosis. Ginekol Pol. 2020; 91(4): 189-192.
  20. Ueki M, Tsurunaga T, Ushiroyama T, Ueda M. Macrophage acti­vation factors and cytokines in peritoneal fluid from patients with endometriosis. Asia Oceania J Obstet Gynaecol. 1994; 20(4): 427- 431.
  21. Wang XM, Ma ZY, Song N. Inflammatory cytokines IL-6, IL-10, IL-13, TNF-α and peritoneal fluid flora were associated with infertility in pa­tients with endometriosis. Eur Rev Med Pharmacol Sci. 2018; 22(9): 2513-2518.
  22. Socolov R, Socolov D, Sindilar A, Pavaleanu I. An update on the biological markers of endometriosis. Minerva Ginecol. 2017; 69(5): 462-467.
  23. Kaur S, Bansal Y, Kumar R, Bansal G. A panoramic review of IL-6: Structure, pathophysiological roles and inhibitors. Bioorg Med Chem. 2020; 28(5): 115327.
  24. Wang F, Wang H, Jin D, Zhang Y. Serum miR-17, IL-4, and IL-6 levels for diagnosis of endometriosis. Medicine (Baltimore). 2018; 97(24): e10853.
  25. Jiang J, Jiang Z, Xue M. Serum and peritoneal fluid levels of interleu­kin-6 and interleukin-37 as biomarkers for endometriosis. Gynecol Endocrinol. 2019; 35(7): 571-575.
  26. Prins JR, Marissen LM, Scherjon SA, Hoek A, Cantineau AEP. Is there an immune modulating role for follicular fluid in endometriosis? A narrative review. Reproduction. 2020; 159(1): R45-R54.
  27. Ayaub EA, Tandon K, Padwal M, Imani J, Patel H, Dubey A, et al. IL-6 mediates ER expansion during hyperpolarization of alternatively activated macrophages. Immunol Cell Biol. 2019; 97(2): 203-217.
  28. Song Y, Su RW, Joshi NR, Kim TH, Lessey BA, Jeong JW, et al. Interleukin-6 (IL-6) activates the NOTCH1 signaling pathway through E-proteins in endometriotic lesions. J Clin Endocrinol Metab. 2020; 105(5): 1316-1326.
  29. Cheng X, Liu J, Shan H, Sun L, Huang C, Yan Q, et al. Activating transcription factor 3 promotes embryo attachment via up-regulation of leukemia inhibitory factor in vitro. Reprod Biol Endocrinol. 2017; 15(1): 42.
  30. Schmitz CR, Oehninger S, Genro VK, Chandra N, Lattanzio F, Yu L, et al. Alterations in expression of endometrial milk fat globule-EGF factor 8 (MFG-E8) and leukemia inhibitory factor (LIF) in patients with infertility and endometriosis. JBRA Assist Reprod. 2017; 21(4): 313-320.
  31. Yoo I, Chae S, Han J, Lee S, Kim HJ, Ka H. Leukemia inhibitory factor and its receptor: expression and regulation in the porcine en­dometrium throughout the estrous cycle and pregnancy. Asian-Aus­tralas J Anim Sci. 2019; 32(2): 192-200.
  32. Yue X, Wu L, Hu W. The regulation of leukemia inhibitory factor. Can­cer Cell Microenviron. 2015; 2(3): e877.
  33. Zhao Y, He D, Zeng H, Luo J, Yang S, Chen J, et al. Expression and significance of miR-30d-5p and SOCS1 in patients with recurrent implantation failure during implantation window. Reprod Biol Endo­crinol. 2021; 19(1): 138.
  34. Massimiani M, Lacconi V, La Civita F, Ticconi C, Rago R, Campagno­lo L. Molecular signaling regulating endometrium-blastocyst cross­talk. Int J Mol Sci. 2019; 21(1): 23.
  35. Carvalho LFP, Hui CYY, Agarwal A. Endometriosis and infertility: biomarkers affecting implantation rate. Expert Rev Obstet Gynecol. 2013; 8(5): 467-473.
  36. Mehri N, Jamshidizad A, Ghanei Z, Karkhane AA, Shamsara M. Optimizing the expression and solubilization of an E. coli-produced leukemia inhibitory factor for anti-LIF antibody production and use thereof for contraception in mice. Mol Biotechnol. 2021; 63(12): 1169-1182.
  37. Prima AT, Hendry D, Bachtiar H. Correlation between levels of in­terleukin-6 in peritoneal fluid with degree of pain, adhesion, and en­dometriosis fertility index score in endometriosis. AOJ. 2021; 5(2): 193-205.
  38. Altun T, Jindal S, Greenseid K, Shu J, Pal L. Low follicular fluid IL-6 levels in IVF patients are associated with increased likelihood of clini­cal pregnancy. J Assist Reprod Genet. 2011; 28(3): 245-251.