Journal of Assisted Reproduction and Genetics

, Volume 35, Issue 6, pp 1019–1025 | Cite as

Interleukin 15 concentrations in follicular fluid and their effect on oocyte maturation in subfertile women undergoing intracytoplasmic sperm injection

  • S. Spanou
  • D. Kalogiannis
  • E. Zapanti
  • M. Gazouli
  • I. A. Sfontouris
  • C. Siristatidis
  • George Mastorakos
Reproductive Physiology and Disease



To calculate the concentrations of interleukin 15 (IL-15) in follicular fluid (FF) and evaluate their relation with oocyte maturation, follicle size, and patients’ body mass index (BMI) and age.


Follicular fluid specimens were obtained from 56 subfertile women undergoing intracytoplasmic sperm injection (ICSI) during oocyte retrieval for measurement of IL-15 concentrations with ELISA. Wilcoxon’s test and Pearson’s correlation coefficient were used to correlate FF concentrations of IL-15 with follicular size and stage of oocyte maturation, along with patients’ BMI and age.


IL-15 concentrations in FF of follicles with immature oocytes were significantly greater than those from follicles with mature ones (median 5.333 vs. 3.250 pg/ml, respectively, p < 0.001). There was a significant negative correlation between IL-15 concentrations and follicle size (r = − 0.333, p = 0.003). No significant correlation was observed between IL-15 concentrations and patients’ BMI and age (p > 0.05).


IL-15 concentrations in FF are adversely related with the size of the follicles and the maturity of the corresponding retrieved oocytes in a cohort of expected normal responders undergoing intracytoplasmic sperm injection (ICSI). Follicular fluid concentrations of IL-15 should be investigated as a possible predictive factor for oocyte maturity.


IL-15 Follicular fluid Oocyte maturation Cytokines 


Compliance with ethical standards

Conflict of interest

All authors declare no conflict of interest.


  1. 1.
    Fortune JE. Ovarian follicular growth and development in mammals. Biol Reprod. 1994;50:225–32.CrossRefPubMedGoogle Scholar
  2. 2.
    Mendoza C, Cremades N, Ruiz-Requena E, Martinez F, Ortega E, Bernabeu S, et al. Relationship between fertilization results after intracytoplasmatic sperm injection, and intrafollicular steroid, pituitary hormone and cytokine concentrations. Hum Reprod. 1999;14(3):628–35.CrossRefPubMedGoogle Scholar
  3. 3.
    Mendoza C, Ruiz-Requena E, Ortega E, Cremades N, Martinez F, Bernabeu R, et al. Follicular fluid markers of oocyte developmental potential. Hum Reprod. 2002;17:1017–22.CrossRefPubMedGoogle Scholar
  4. 4.
    Ledur A, Fitting C, David B, Hamberger C, Cavaillon JM. Variable estimates of cytokine levels produced by commercial ELISA kits: results using international cytokine standards. J Immunol Methods. 1995;186:171–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Aziz N, Nishanian P, Mitsuyasu R, Detels R, Fahey JL. Variables that affect assays for plasma cytokines and soluble activation markers. Clin Diagn Lab Immunol. 1999;6:89–95.PubMedPubMedCentralGoogle Scholar
  6. 6.
    Whiteside TL. Cytokine assays. Biotechniques. 2002;Suppl:4–8, 10, 12–5.Google Scholar
  7. 7.
    Vujisic S, Lepej SZ, Emedi I, Bauman R, Remenar A, Tiljak MK. Ovarian follicular concentration of IL 12, IL-15, IL-18 and p40 subunit of IL-12 and IL-23. Hum Reprod. 2006;21(10):2650–5.CrossRefPubMedGoogle Scholar
  8. 8.
    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):336–42.CrossRefPubMedGoogle Scholar
  9. 9.
    Lédée N, Frydman R, Osipova A, Taieb J, Gallot V, Lombardelli L, et al. Levels of follicular G-CSF and interleukin-15 appear as noninvasive biomarkers of subsequent successful birth in modified natural in vitro fertilization/ intracytoplasmic sperm injection cycles. Fertil Steril. 2011;95(1):94–108.CrossRefPubMedGoogle Scholar
  10. 10.
    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):357–64.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Larsson A, Carlsson L, Lind AL, Gordh T, Bodolea C, Kamali-Moghaddam M, et al. The body mass index (BMI) is significantly correlated with levels of cytokines and chemokines in cerebrospinal fluid. Cytokine. 2015;76(2):514–8.CrossRefPubMedGoogle Scholar
  12. 12.
    De Filippo G, Rendina D, Moccia F, Rocco V, Campanozzi A. Interleukin-6, soluble interleukin-6 receptor/interleukin-6 complex and insulin resistance in obese children and adolescents. J Endocrinol Investig. 2015;38(3):339–43.CrossRefGoogle Scholar
  13. 13.
    Bonetti T, Klaine J, Salomao R, Braga D, Borges E, Silva I. The levels of hormones and cytokines in follicular fluid are associated with body mass index, independently of age and dose of gonadotropin administered. Fertil Steril. 2010;94(4):64.CrossRefGoogle Scholar
  14. 14.
    Bou Nemer L, Word A, Carr B, Bukulmez O. Impact of body mass index on levels of soluble interleukin-6 receptor in follicular fluid of women undergoing in-vitro fertilization. Fertil Steril. 2017;107(3):7.CrossRefGoogle Scholar
  15. 15.
    Oppenheim JJ, Ruscetti FW, Faltynek C. Basic and clinical immunology: cytokines. In: DP Stites, AI Terr, editors. 7th ed. East Norwalk: Appleton and Lange; 1991. p 78.Google Scholar
  16. 16.
    Kaipia A, Hsueh AJ. Regulation of ovarian follicle atresia. Annu Rev Physiol. 1997;59:349–63.CrossRefPubMedGoogle Scholar
  17. 17.
    Field SL, Dasgupta T, Cummings M, Orsi NM. Cytokines in ovarian folliculogenesis, oocyte maturation and luteinisation. Mol Reprod Dev. 2014;81(4):284–314.CrossRefPubMedGoogle Scholar
  18. 18.
    Shimasaki S, Moore RK, Erickson GF, Otsuka F. The role of bone morphogenetic proteins in ovarian function. Reprod Suppl. 2003;61:323–37.PubMedGoogle Scholar
  19. 19.
    Bornstein SR, Rutkowski H, Vrezas I. Cytokines and steroidogenesis. Mol Cell Endocrinol. 2004;215:135–41.CrossRefPubMedGoogle Scholar
  20. 20.
    Bristol SK, Woodruff TK. Follicle-restricted compartmentalization of transforming growth factor beta superfamily ligands in the feline ovary. Biol Reprod. 2004;70:846–59.CrossRefPubMedGoogle Scholar
  21. 21.
    McNatty KP, Smith P, Moore LG, Reader K, Lun S, Hanrahan JP, et al. Oocyte expressed genes affecting ovulation rate. Mol Cell Endocrinol. 2005;234:57–66.CrossRefPubMedGoogle Scholar
  22. 22.
    Knight PG, Glister C. TGF-beta superfamily members and ovarian follicle development. Reproduction. 2006;132:191–206.CrossRefPubMedGoogle Scholar
  23. 23.
    Di Sabatino A, Calarota SA, Vidali F, Macdonald TT, Corazza GR. Role of IL-15 in immune-mediated and infectious diseases. Cytokine Growth Factor Rev. 2011;22(1):19–23.CrossRefPubMedGoogle Scholar
  24. 24.
    Steel JC, Waldmann TA, Morris JC. Interleukin 15 biology and its therapeutic implications in cancer. Trends Pharmacil Sci. 2012;33(1):35–41.CrossRefGoogle Scholar
  25. 25.
    Di Spiezio SA, Di Carlo C, Minozzi S, Spinelli M, Pistotti V, Alviggi C, et al. Efficacy of hysteroscopy in improving reproductive outcomes of infertile couples: a systematic review and meta-analysis. Hum Reprod Update. 2016 Jun;22(4):479–96.CrossRefGoogle Scholar
  26. 26.
    Bosteels J, Kasius J, Weyers S, Broekmans FJ, Mol BW, D'Hooghe TM. Hysteroscopy for treating subfertility associated with suspected major uterine cavity abnormalities. Cochrane Database Syst Rev. 2015;(2):CD009461.Google Scholar
  27. 27.
    Wittmaack FM, Kreger DO, Blasco L, Tureck RW, Mastroianni L Jr, Lessey BA. Effect of follicular size on oocyte retrieval, fertilization, cleavage, and embryo quality in in vitro fertilization cycles: a 6-year data collection. Fertil Steril. 1994;62(6):1205–10.CrossRefPubMedGoogle Scholar
  28. 28.
    Ghizzoni L, Mastorakos G, Vottero A, Barreca A, Furlini M, Cesarone A, et al. Corticotropin-releasing hormone (CRH) inhibits steroid biosynthesis by cultured human granulosa-lutein cells in a CRH and interleukin-1 receptor-mediated fashion. Endocrinology. 1997;38(11):4806–11.CrossRefGoogle Scholar
  29. 29.
    Hammadeh ME, Fischer-Hammadeh C, Georg T, Rosenbaum P, Schmidt W. Comparison between cytokine concentration in follicular fluid of poor and high responder patients and their influence of ICSI-outcome. Am J Reprod Immunol. 2003;50:131–6.CrossRefPubMedGoogle Scholar
  30. 30.
    Hammadeh ME, Fischer-Hammadeh C, Hoffmeister H, Herrmann V, Rosenbaum P, Schmidt W. Relationship between cytokine concentrations (FGF, sICAM-1 and SCF) in serum, follicular fluid and ICSI outcome. Am J Reprod Immunol. 2004;51:81–5.CrossRefPubMedGoogle Scholar
  31. 31.
    Xin L, Rui J, Fang W, Bo J, Kang L, Feng-Wei C, et al. Interleukin-15 inhibits the expression of differentiation markers induced by Ca2+ in keratinocytes. Exp Dermatol. 2016;25(7):544–7.CrossRefGoogle Scholar
  32. 32.
    Ramaswamy S, Nakamura N, Vazquez F, Batt DB, Perera S, Roberts TM, et al. Regulation of G1 progression by the PTEN tumor suppressor protein is linked to inhibition of the phosphatidylinositol 3-kinase/Akt pathway. Proc Natl Acad Sci U S A. 1999;96(5):2110–5.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Kandel ES, Skeen J, Majewski N, Di Cristofano A, Pandolfi PP, Feliciano CS, et al. Activation of Akt/protein kinase B overcomes a G (2)/m cell cycle checkpoint induced by DNA damage. Mol Cell Biol. 2002;22(22):7831–41.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Boni R, Gualtieri R, Talevi R, Tosti E. Calcium and other ion dynamics during gamete maturation and fertilization. Theriogenology. 2007;68:156–64.CrossRefGoogle Scholar
  35. 35.
    Ahmad K, Bracho GE, Wolf DP, Tash JS. Regulation of human sperm motility and hyperactivation components by calcium, calmodulin, and protein phosphatases. Arch Androl. 1995;35:187–208.CrossRefPubMedGoogle Scholar
  36. 36.
    Ectors FJ, Vanderzwalmen P, Van Hoeck J, Nijs M, Verhaegen G, Delvigne A, et al. Relationship of human follicular diameter with oocyte fertilization and development after in-vitro fertilization or intracytoplasmic sperm injection. Hum Reprod. 1997;12(9):2002–5.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • S. Spanou
    • 1
  • D. Kalogiannis
    • 2
  • E. Zapanti
    • 3
  • M. Gazouli
    • 4
  • I. A. Sfontouris
    • 5
    • 6
  • C. Siristatidis
    • 7
  • George Mastorakos
    • 1
  1. 1.Unit of Endocrinology, Diabetes Mellitus and Metabolism, Aretaieion Hospital, Medical SchoolNational and Kapodistrian University of AthensAthensGreece
  2. 2.Faculty of Animal Science and Aquaculture, Department of Anatomy and Physiology of Farm AnimalsAgricultural University of AthensAthensGreece
  3. 3.Department of Endocrinology and DiabetesAlexandra HospitalAthensGreece
  4. 4.Laboratory of Biology, Department of Basic Medical Sciences, Medical SchoolNational and Kapodistrian University of AthensAthensGreece
  5. 5.Eugonia Assisted Reproduction UnitAthensGreece
  6. 6.Division of Child Health, Obstetrics and Gynaecology, School of MedicineUniversity of NottinghamNottinghamUK
  7. 7.Assisted Reproduction Unit, Third Department of Obstetrics and Gynecology, Attikon Hospital, Medical SchoolNational and Kapodistrian University of AthensAthensGreece

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