Skip to main content
Log in

Interleukin 6 in follicular fluid reduces embryo fragmentation and improves the clinical pregnancy rate

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

Abstract

Purpose

The aim of this study was to evaluate the role of interleukin 6 in embryo development in the in vitro fertilization cycles.

Methods

This was a retrospective cohort study. One hundred and three women undergoing in vitro fertilization and embryo transfer due to a tubal factor were included in the study. The follicular fluid IL-6 levels on oocyte retrieval day from each patient were determined by ELISA. The relationships between follicular fluid IL-6 levels and IVF cycle parameters were investigated.

Results

The levels of follicular fluid IL-6 were not affected by the use of drugs for superovulation or by estrogen. In addition, follicular fluid IL-6 levels did not affect the number of oocytes retrieved or the MII oocyte rate. High levels of follicular fluid IL-6 correlated with a significant increase in the rates of clinical pregnancy. Follicular fluid IL-6 levels did not affect the cell number or the blastomere symmetry of day 3 embryos, but it did significantly reduce the embryo fragmentation rate.

Conclusions

High levels of follicular fluid IL-6 improved the rates of clinical pregnancy and reduce embryo fragmentation.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Garbers C, Heink S, Korn T, Rose-John S. Interleukin-6: designing specific therapeutics for a complex cytokine. Nat Rev Drug Discov. 2018;17:395–412.

    Article  CAS  PubMed  Google Scholar 

  2. Mihaela P, Cătălina B, Adela P, Dumitriţa R, Corina I. Antiangiogenic cytokines as potential new therapeutic targets for resveratrol in diabetic retinopathy. Drug Des Devel Ther. 2018;12:1985–96.

    Article  Google Scholar 

  3. Jones ASK, Shikanov A. Follicle development as an orchestrated signaling network in a 3D organoid. J Biol Eng. 2019;13:2.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Buyalos RP, Watson JM, Martinez-Maza O. Detection of interleukin-6 in human follicular fluid. Fertil Steril. 1992;57:1230–4.

    Article  CAS  PubMed  Google Scholar 

  5. Kollmann Z, Schneider S, Fux M, Bersinger NA, von Wolff M. Gonadotrophin stimulation in IVF alters the immune cell profile in follicular fluid and the cytokine concentrations in follicular fluid and serum. Hum Reprod. 2017;32:820–31.

    Article  CAS  PubMed  Google Scholar 

  6. 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;34:357–64.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Baskind NE, Orsi NM, Sharma V. Follicular-phase ovarian follicular fluid and plasma cytokine profiling of natural cycle in vitro fertilization patients. Fertil Steril. 2014;102:410–8.

    Article  CAS  PubMed  Google Scholar 

  8. Field SL, Dasgupta T, Cummings M, Orsi NM. Cytokines in ovarian folliculogenesis, oocyte maturation and luteinisation. Mol Reprod Dev. 2014;81:284–314.

    Article  CAS  PubMed  Google Scholar 

  9. 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 

  10. DeMatos D, Tran CA, Kagan D, Nataraja S, Palmer S. Interleukin-6 (IL-6) induces cumulus expansion and improves oocyte competence when present during mouse in vitro oocyte maturation (IVM). Biol Reprod. 2008;78:311.

    Article  Google Scholar 

  11. Qin L, Xu W, Li X, Meng W, Hu L, Luo Z, et al. Differential expression profile of immunological cytokines in local ovary in patients with polycystic ovarian syndrome: analysis by flow Cytometry. Eur J Obstet Gynecol Reprod Biol. 2016;197:136–41.

    Article  CAS  PubMed  Google Scholar 

  12. Liu Z, de Matos DG, Fan HY, Shimada M, Palmer S, Richards JS. Interleukin-6: an autocrine regulator of the mouse cumulus cell-oocyte complex expansion process. Endocrinology. 2009;150:3360–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wu R, Fujii S, Ryan NK, Van der Hoek KH, Jasper MJ, Sini I, et al. Ovarian leukocyte distribution and cytokine/chemokine mRNA expression in follicular fluid cells in women with polycystic ovary syndrome. Hum Reprod. 2007;22:527–35.

    Article  CAS  PubMed  Google Scholar 

  14. 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;28:245–51.

    Article  PubMed  Google Scholar 

  15. Bou Nemer L, Shi H, Carr BR, Word RA, Bukulmez O. Effect of single-dose ibuprofen on follicular fluid levels of interleukins in poor responders undergoing in vitro fertilization. Syst Biol Reprod Med. 2019;65:48–53.

    Article  CAS  PubMed  Google Scholar 

  16. Semeniuk LM, Likhachov VK, Yuzvenko TY, Dobrovolska Lcapital Em C, Makarov OG. Risk markers of reproductive loss in women with hyperandrogenism. Wiad Lek. 2018;71:1550–3.

    PubMed  Google Scholar 

  17. Banerjee J, Sharma R, Agarwal A, Maitra D, Diamond MP, Abu-Soud HM. IL-6 and mouse oocyte spindle. PLoS One. 2012;7:e35535.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Alhilali MJS, Parham A, Attaranzadeh A, Amirian M, Azizzadeh M. IL-5 in follicular fluid as a negative predictor of the intracytoplasmic sperm injection outcome. Cytokine. 2019;113:265–71.

    Article  CAS  PubMed  Google Scholar 

  19. 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;33:1363–72.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Asimakopoulos B, Abu-Hassan D, Metzen E, Al-Hasani S, Diedrich K, Nikolettos N. The levels of steroid hormones and cytokines in individual follicles are not associated with the fertilization outcome after intracytoplasmic sperm injection. Fertil Steril. 2008;90:60–4.

    Article  CAS  PubMed  Google Scholar 

  21. Hammadeh ME, Ertan AK, Zeppezauer M, Baltes S, Georg T, Rosenbaum P, et al. Immunoglobulins and cytokines level in follicular fluid in relation to etiology of infertility and their relevance to IVF outcome. Am J Reprod Immunol. 2002;47:82–90.

    Article  PubMed  Google Scholar 

  22. Hammadeh ME, Braemert B, Baltes S, Georg T, Rosenbaum P, Schmidt W. Relationship between ovarian stimulation regimen and cytokine concentration in follicular fluid and their effect on fertilization and pregnancy outcome of patients undergoing ICSI program. Am J Reprod Immunol. 2000;43:12–20.

    Article  CAS  PubMed  Google Scholar 

  23. Bedaiwy M, Shahin AY, AbulHassan AM, Goldberg JM, Sharma RK, Agarwal A, 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 

  24. Ferraretti AP, La Marca A, Fauser BC, Tarlatzis B, Nargund G, Gianaroli L. ESHRE consensus on the definition of 'poor response' to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum Reprod. 2011;26:1616–24.

    Article  CAS  PubMed  Google Scholar 

  25. Cutting R, Morroll D, Roberts SA, Pickering S, Rutherford A. Elective single embryo transfer: guidelines for practice British Fertility Society and Association of Clinical Embryologists. Hum Fertil (Camb). 2008;11:131–46.

    Article  Google Scholar 

  26. The Istanbul consensus workshop on embryo assessment: proceedings of an expert meeting. Hum Reprod. 2011;26:1270–83.

  27. Maeda A, Goto Y, Matsuda-Minehata F, Cheng Y, Inoue N, Manabe N. Changes in expression of interleukin-6 receptors in granulosa cells during follicular atresia in pig ovaries. J Reprod Dev. 2007;53:727–36.

    Article  CAS  PubMed  Google Scholar 

  28. Molyneaux KA, Schaible K, Wylie C. GP130, the shared receptor for the LIF/IL6 cytokine family in the mouse, is not required for early germ cell differentiation, but is required cell-autonomously in oocytes for ovulation. Development. 2003;130:4287–94.

    Article  CAS  PubMed  Google Scholar 

  29. Burns KA, Thomas SY, Hamilton KJ, Young SL, Cook DN, Korach KS. Early endometriosis in females is directed by immune-mediated estrogen receptor alpha and IL-6 cross-talk. Endocrinology. 2018;159:103–18.

    Article  CAS  PubMed  Google Scholar 

  30. Hammadeh ME, Ertan AK, Georg MT, Rosenbaum P, Schmidt W. Relationship between ovarian stimulation regimen and interleukin level in pre-ovulatory follicular fluid and their effect on ICSI outcome. Am J Reprod Immunol. 2002;48:255–61.

    Article  CAS  PubMed  Google Scholar 

  31. Dominguez F, Meseguer M, Aparicio-Ruiz B, Piqueras P, Quinonero A, Simon C. New strategy for diagnosing embryo implantation potential by combining proteomics and time-lapse technologies. Fertil Steril. 2015;104:908–14.

    Article  PubMed  Google Scholar 

  32. Stensen MH, Tanbo TG, Storeng R, Abyholm T, Fedorcsak P. Fragmentation of human cleavage-stage embryos is related to the progression through meiotic and mitotic cell cycles. Fertil Steril. 2015;103:374–81.

    Article  PubMed  Google Scholar 

  33. Chi HJ, Koo JJ, Choi SY, Jeong HJ, Roh SI. Fragmentation of embryos is associated with both necrosis and apoptosis. Fertil Steril. 2011;96:187–92.

    Article  PubMed  Google Scholar 

  34. Shen XH, Han YJ, Zhang DX, Cui XS, Kim NH. A link between the interleukin-6/Stat3 anti-apoptotic pathway and microRNA-21 in preimplantation mouse embryos. Mol Reprod Dev. 2009;76:854–62.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was funded by the Scientific Research Foundation of Yunnan Provincial Education Department (Item Number: 2019 J1256) and Construction Project of 135 Key Specialized Subjects in Kunming Medical University (Item Number: J1301819).

Author information

Authors and Affiliations

Authors

Contributions

Conceptualization: [Yushi Meng]; Methodology: [Hong Yang], [Yang Bai], [Hao Zha]; Formal analysis and investigation: [Fangjie Jiang]; Writing - original draft preparation: [Jie Yang]; Writing - review and editing: [Xiaoling Yang].

Corresponding author

Correspondence to Yushi Meng.

Ethics declarations

The study was approved by the Institutional Review Board of the Second Affiliated Hospital of Kunming Medical University and informed written consent was obtained from all patients.

Conflict of interest

The authors’ declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the Institutional Review Board of the Second Affiliated Hospital of Kunming Medical University and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Yang, J., Yang, X., Yang, H. et al. Interleukin 6 in follicular fluid reduces embryo fragmentation and improves the clinical pregnancy rate. J Assist Reprod Genet 37, 1171–1176 (2020). https://doi.org/10.1007/s10815-020-01737-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10815-020-01737-2

Keywords

Navigation