Skip to main content

Advertisement

SpringerLink
Log in

Intrafollicular interleukin-8, interleukin-12, and adrenomedullin are the promising prognostic markers of oocyte and embryo quality in women with endometriosis

  • Assisted Reproduction Technologies
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

The study aimed to investigate key intrafollicular prognostic factors among various cytokines and angiogenic molecules for prediction of mature oocytes and good-quality embryos in women with endometriosis undergoing in vitro fertilization (IVF).

Methods

Paired follicular fluid and serum samples were collected from 200 women with advanced stage endometriosis and 140 normal ovulating women during oocyte retrieval. The concentrations of cytokines (pro-inflammatory: IL-1β, TNF-α, IL-2, IL-8, IL-12, IFN-γ; anti-inflammatory: IL-4, IL-6, IL-10) and angiogenic molecules (vascular endothelial growth factor (VEGF), adrenomedullin, angiogenin) were determined in follicular fluid and serum using ELISA. Expression of these molecules was subjected to multivariate analysis for the identification of major predictive markers of oocyte and embryo quality. Receiver operating characteristic (ROC) curve was applied to determine the best cutoff point for the discrimination between mature and immature oocytes in these women.

Results

Significant increases in levels of cytokines and angiogenic molecules were observed in women with endometriosis compared to controls (P < 0.001). From the validated partial least squares-discriminant analysis (PLS-DA) model, IL-8, IL-12, and adrenomedullin were identified as the most important factors contributing to endometriosis and were negatively associated with oocyte maturity and embryo quality.

Conclusion

The levels of IL-8, IL-12, and adrenomedullin may be good indicators of embryo and oocyte quality in endometriosis patients undergoing IVF. Further studies are necessary to ascertain the potential of these markers for oocyte and embryo developmental competence which may help improve the chances of a successful IVF in endometriosis patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Rizk B, Abdalla H. Epidemiology and pathogenesis. Endometriosis. Oxford: Health Press Limited; 2003.

    Google Scholar 

  2. Barnhart K, Dunsmoor-Su R, Coutifaris C. Effect of endometriosis on in vitro fertilization. Fertil Steril. 2002;77:1148–55.

    Article  PubMed  Google Scholar 

  3. Stilley JA, Birt JA, Sharpe-Timms KL. Cellular and molecular basis for endometriosis-associated infertility. Cell Tissue Res. 2012;349:849–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Das S, Chattopadhyay R, Ghosh S, Goswami SK, Chakravarty BN, et al. Reactive oxygen species level in follicular fluid—embryo quality marker in IVF? Hum Reprod. 2006;21:2403–7.

    Article  CAS  PubMed  Google Scholar 

  5. Trombly DJ, Woodruff TK, Mayo KE. Roles for transforming growth factor beta superfamily proteins in early folliculogenesis. Semin Reprod Med. 2009;27:14–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ostanin AA, Aizikovich BI, Aizikovich IV, Kozhin AY, Chernykh ER. Role of cytokines in the regulation of reproductive function. Bull Exp Biol Med. 2007;143:75–9.

    Article  CAS  PubMed  Google Scholar 

  7. Machelon V, Emilie D. Production of ovarian cytokines and their role in ovulation in the mammalian ovary. Eur Cytokine Netw. 1997;8:137–43.

    CAS  PubMed  Google Scholar 

  8. Bornstein SR, Rutkowski H, Vrezas I. Cytokines and steroidogenesis. Mol Cell Endocrinol. 2004;215:135–41.

    Article  CAS  PubMed  Google Scholar 

  9. Sarapik A, Velthut A, Haller-Kikkatalo K, Faure GC, Bene MC, et al. Follicular proinflammatory cytokines and chemokines as markers of IVF success. Clin Dev Immunol. 2012;2012:606459.

    Article  PubMed  Google Scholar 

  10. Fraser HM. Regulation of the ovarian follicular vasculature. Reprod Biol Endocrinol. 2006;4:18.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Malamitsi-Puchner A, Sarandakou A, Baka SG, Tziotis J, Rizos D, et al. Concentrations of angiogenic factors in follicular fluid and oocyte-cumulus complex culture medium from women undergoing in vitro fertilization: association with oocyte maturity and fertilization. Fertil Steril. 2001;76:98–101.

    Article  CAS  PubMed  Google Scholar 

  12. Manau D, Balasch J, Jimenez W, Fabregues F, Civico S, et al. Follicular fluid concentrations of adrenomedullin, vascular endothelial growth factor and nitric oxide in IVF cycles: relationship to ovarian response. Hum Reprod. 2000;15:1295–9.

    Article  CAS  PubMed  Google Scholar 

  13. Garrido N, Navarro J, Garcia-Velasco J, Remoh J, Pellice A, et al. The endometrium versus embryonic quality in endometriosis-related infertility. Hum Reprod Update. 2002;8:95–103.

    Article  CAS  PubMed  Google Scholar 

  14. Pellicer A, Albert C, Garrido N, Navarro J, Remohi J, et al. The pathophysiology of endometriosis-associated infertility: follicular environment and embryo quality. J Reprod Fertil Suppl. 2000;55:109–19.

    CAS  PubMed  Google Scholar 

  15. Lo Turco EG, Souza GH, Garcia JS, Ferreira CR, Eberlin MN, et al. Effect of endometriosis on the protein expression pattern of follicular fluid from patients submitted to controlled ovarian hyperstimulation for in vitro fertilization. Hum Reprod. 2010;25:1755–66.

    Article  PubMed  Google Scholar 

  16. ASRM. Revised American Society for Reproductive Medicine classification of endometriosis: 1996. Fertil Steril. 1997;67:817–21.

    Article  Google Scholar 

  17. WHO. Laboratory manual for the examination of human semen and sperm-cervical mucus interaction. York: Cambridge University Press; 2010. p. 138.

    Google Scholar 

  18. Veeck LL. An atlas of human gametes and conceptuses: an illustrated reference for assisted reproductive technology. New York: Parthenon Publishing; 1999.

    Book  Google Scholar 

  19. Chaudhury K, Chakravarty B. Endometriosis—basic concepts and current research trends. Rijeka: InTech; 2012.

    Book  Google Scholar 

  20. Nouri M, Ghaffari M, Salmasi A, Ghasemzadeh A. Serum and follicular fluid IL-6 and sex steroid hormone levels and their correlation of undergoing IVF-ET with endometriosis and pregnancy rate in women. J Reprod Infertility. 2000;1:55–62.

    Google Scholar 

  21. Pellicer A, Albert C, Mercader A, Bonilla-Musoles F, Remohi J, et al. The follicular and endocrine environment in women with endometriosis: local and systemic cytokine production. Fertil Steril. 1998;70:425–31.

    Article  CAS  PubMed  Google Scholar 

  22. Podgaec S, Dias Junior JA, Chapron C, Oliveira RM, Baracat EC, et al. Th1 and Th2 immune responses related to pelvic endometriosis. Rev Assoc Med Bras. 2010;56:92–8.

    Article  PubMed  Google Scholar 

  23. Yu C, Liu Y, Peng X. IL-8 and IL-10 levels in endometriosis and regulated role of neiyifang on them. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2000;20:603–5.

    CAS  PubMed  Google Scholar 

  24. Galo S, Zubor P, Szunyogh N, Kajo K, Machalekova K, et al. TNF-alpha serum levels in women with endometriosis: prospective clinical study. Ceska Gynekol. 2005;70:286–90.

    CAS  PubMed  Google Scholar 

  25. Arici A. Local cytokines in endometrial tissue: the role of interleukin-8 in the pathogenesis of endometriosis. Ann N Y Acad Sci. 2002;955:101–9. discussion 118, 396-406.

    Article  CAS  PubMed  Google Scholar 

  26. Fairbanks F, Abrao MS, Podgaec S, Dias Jr JA, de Oliveira RM, et al. Interleukin-12 but not interleukin-18 is associated with severe endometriosis. Fertil Steril. 2009;91:320–4.

    Article  CAS  PubMed  Google Scholar 

  27. Gosden RG, Hunter RH, Telfer E, Torrance C, Brown N. Physiological factors underlying the formation of ovarian follicular fluid. J Reprod Fertil. 1988;82:813–25.

    Article  CAS  PubMed  Google Scholar 

  28. Bili H, Tarlatzis BC, Daniilidis M, Fleva A, Bontis J, et al. Cytokines in the human ovary: presence in follicular fluid and correlation with leukotriene B4. J Assist Reprod Genet. 1998;15:93–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Barrionuevo MJ, Schwandt RA, Rao PS, Graham LB, Maisel LP, et al. Nitric oxide (NO) and interleukin-1beta (IL-1beta) in follicular fluid and their correlation with fertilization and embryo cleavage. Am J Reprod Immunol. 2000;44:359–64.

    Article  CAS  PubMed  Google Scholar 

  30. Bedaiwy M, Shahin AY, AbulHassan AM, Goldberg JM, Sharma RK, et al. Differential expression of follicular fluid cytokines: relationship to subsequent pregnancy in IVF cycles. Reprod Biomed Online. 2007;15:321–5.

    Article  CAS  PubMed  Google Scholar 

  31. Kawasaki F, Kawano Y, Kosay Hasan Z, Narahara H, Miyakawa I. The clinical role of interleukin-6 and interleukin-6 soluble receptor in human follicular fluids. Clin Exp Med. 2003;3:27–31.

    Article  CAS  PubMed  Google Scholar 

  32. Spandorfer SD, Neuer A, Liu HC, Rosenwaks Z, Witkin SS. Involvement of interleukin-1 and the interleukin-1 receptor antagonist in in vitro embryo development among women undergoing in vitro fertilization-embryo transfer. J Assist Reprod Genet. 2003;20:502–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ledee N, Lombroso R, Lombardelli L, Selva J, Dubanchet S, et al. Cytokines and chemokines in follicular fluids and potential of the corresponding embryo: the role of granulocyte colony-stimulating factor. Hum Reprod. 2008;23:2001–9.

    Article  CAS  PubMed  Google Scholar 

  34. Gazvani MR, Bates M, Vince G, Christmas S, Lewis-Jones DI, et al. Follicular fluid concentrations of interleukin-12 and interleukin-8 in IVF cycles. Fertil Steril. 2000;74:953–8.

    Article  CAS  PubMed  Google Scholar 

  35. Lee KS, Joo BS, Na YJ, Yoon MS, Choi OH, et al. Relationships between concentrations of tumor necrosis factor-alpha and nitric oxide in follicular fluid and oocyte quality. J Assist Reprod Genet. 2000;17:222–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wunder DM, Mueller MD, Birkhauser MH, Bersinger NA. Increased ENA-78 in the follicular fluid of patients with endometriosis. Acta Obstet Gynecol Scand. 2006;85:336–42.

    Article  CAS  PubMed  Google Scholar 

  37. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Cytokine Growth Factor Rev. 2001;12:53–72.

    Article  CAS  PubMed  Google Scholar 

  38. Giudice LC. Clinical practice. Endometriosis. N Engl J Med. 2010;362:2389–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Hammadeh ME, Fischer-Hammadeh C, Hoffmeister H, Huebner U, Georg T, et al. Fibroblast growth factor (FGF), intracellular adhesion molecule (sICAM-1) level in serum and follicular fluid of infertile women with polycystic ovarian syndrome, endometriosis and tubal damage, and their effect on ICSI outcome. Am J Reprod Immunol. 2003;50:124–30.

    Article  CAS  PubMed  Google Scholar 

  40. Monteleone P, Giovanni Artini P, Simi G, Casarosa E, Cela V, et al. Follicular fluid VEGF levels directly correlate with perifollicular blood flow in normoresponder patients undergoing IVF. J Assist Reprod Genet. 2008;25:183–6.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Kung FT, Chang SY, Huang FJ, Lan KC. VEGF, IVF clinical variables and ovarian hyperstimulation syndrome: a prospective study of the preimplantation luteal phase. J Reprod Med. 2007;52:365–74.

    CAS  PubMed  Google Scholar 

  42. Marinoni E, Di Iorio R, Villaccio B, Letizia C, Aragona C, et al. Follicular fluid adrenomedullin concentrations in spontaneous and stimulated cycles: relationship to ovarian function and endothelin-1 and nitric oxide. Regul Pept. 2002;107:125–8.

    Article  CAS  PubMed  Google Scholar 

  43. Gao MZ, Zhao XM, Lin Y, Sun ZG, Zhang HQ. Effects of EG-VEGF, VEGF and TGF-beta1 on pregnancy outcome in patients undergoing IVF-ET treatment. J Assist Reprod Genet. 2012;29:1091–6.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Marinoni E, Feliciani E, Muzzonigro F, Letizia C, Tranquilli A, et al. Intrafollicular concentration of adrenomedullin is associated with IVF outcome. Gynecol Endocrinol. 2010;26:435–9.

    Article  CAS  PubMed  Google Scholar 

  45. Jana SK, Banerjee P, Mukherjee R, Chakravarty B, Chaudhury K. HOXA-11 mediated dysregulation of matrix remodeling during implantation window in women with endometriosis. J Assist Reprod Genet. 2013;30:1505–12.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Wei Q, St Clair JB, Fu T, Stratton P, Nieman LK. Reduced expression of biomarkers associated with the implantation window in women with endometriosis. Fertil Steril. 2009;91:1686–91.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The first author is grateful to the Government of India, Indian Council of Medical Research for financial support under the ICMR-JRF scheme. The authors are grateful to all the volunteers who participated in this study, as well as to Gunja Bose from IRM, Kolkata for helping in collection of samples.

Author information

Authors and Affiliations

  1. School of Medical Science and Technology, Indian Institute of Technology, Kharagpur, West Bengal, 721302, India

    Abhay Kumar Singh, Mainak Dutta & Koel Chaudhury

  2. Institute of Reproductive Medicine, Salt Lake, Kolkata, West Bengal, 700020, India

    Ratna Chattopadhyay & Baidyanath Chakravarty

Authors
  1. Abhay Kumar Singh
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mainak Dutta
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ratna Chattopadhyay
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Baidyanath Chakravarty
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Koel Chaudhury
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Koel Chaudhury.

Additional information

Capsule

Levels of IL-8, IL-12, and adrenomedullin as good indicators of embryo and oocyte quality in women with endometriosis undergoing IVF

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Singh, A.K., Dutta, M., Chattopadhyay, R. et al. 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 33, 1363–1372 (2016). https://doi.org/10.1007/s10815-016-0782-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-016-0782-5

Keywords

Search

Navigation