Skip to main content
PMC home page
Journal of Assisted Reproduction and Genetics logoLink to Journal of Assisted Reproduction and Genetics
. 1999 May;16(5):247–252. doi: 10.1023/A:1020363312252

Cytokines in Older Patients Undergoing In Vitro Fertilization: The Relationship to the Response to Controlled Ovarian Hyperstimulation

Antonio Pellicer 1,2,✉, Nicolás Garrido 1, Carmela Albert 1, José Navarro 1, José Remohí 1,2, Carlos Simón 1,2
PMCID: PMC3455706  PMID: 10335471

Abstract

Purpose:Our purpose was to assess the endocrine, autocrine, and paracrine milieu in follicles of older women undergoing stimulated cycles, comparing normal (NR) and low (LR) responses, based on the measurement of interleukin (IL)-1β, IL-6, and vascular endothelial growth factor (VEGF) in serum and follicular fluid (FF).

Methods:A total of 40 women entered the study, divided into three groups: (1) older patients (>37 years) with NR (age-NR; n = 18); (2) older women with LR (age-LR; n = 11); and (3) normal controls, aged <35 years (control; n = 11). IL-1β, IL-6, and VEGF measured in serum (day of ovum pickup) and FF, employing ELISAs.

Results:Follicular fluid IL-6 was significantly (P < 0.05) higher in age-LR compared to the other two groups. IL-6 and VEGF showed a 4- to 20-fold increase in FF compared to blood, suggesting the ovary as an additional source of both cytokines. IL-1β levels remained unchanged in FF compared to blood and, also, among groups.

Conclusions:These data provide further evidence that the endocrine, paracrine, and/or autocrine status in vivo of older patients is different from that of younger women and suggest that cytokines, specifically IL-6, may be involved in the changes observed during senescence within the ovary.

Keywords: age, low responders, follicular fluid, serum, interleukin-1β, interleukin-6, vascular endothelial growth factor

Full Text

The Full Text of this article is available as a PDF (508.7 KB).

REFERENCES

  • 1.Menken J, Trussell J, Larsen U. Age and Infertility. Science. 1986;233:1389–1394. doi: 10.1126/science.3755843. [DOI] [PubMed] [Google Scholar]
  • 2.Pellicer A, Marí M, de los Santos S. C., Remohi J, Tarin JJ. Effects of aging on the human ovary: The secretion of immunoreactive α-inhibin and progesterone. Fertil. Steril. 1994;61:663–668. doi: 10.1016/s0015-0282(16)56643-6. [DOI] [PubMed] [Google Scholar]
  • 3.Klein NA, Illingwort PJ, Groome NP, McNeilly AS, Battaglia DE, Soules MR. Decreased inhibin B secretion is associated wit the monotropic FSH rise in older, ovulatory women: A study of serum and follicular fluid levels of dimeric inhibin A and B in spontaneous menstrual cycles. J Clin Endocrinol Metab. 1996;81:2742–2745. doi: 10.1210/jcem.81.7.8675606. [DOI] [PubMed] [Google Scholar]
  • 4.Seifer DB, Gardiner AC, Lambert-Messerlian G, Schneyer AL. Differential secretion of dimeric inhibin in cultured luteinized granulosa cells as a function of ovarian reserve. J Clin Endocrinol Metab. 1996;81:736–739. doi: 10.1210/jcem.81.2.8636296. [DOI] [PubMed] [Google Scholar]
  • 5.Pellicer A, Ballester MJ, Serrano MD, Mir A, Serra-Serra V, Remohi J, Bonilla-Musoles FM. Aetiologic factors involved in the low response to gonadotrophins in infertile women with normal basal serum follicle stimulating hormone. Hum Reprod. 1994;9:806–811. doi: 10.1093/oxfordjournals.humrep.a138600. [DOI] [PubMed] [Google Scholar]
  • 6.Simón C, Tsafriri A, Pellicer A, Polan ML. The role of interleukins in the ovary. Reprod Med Rev. 1996;5:51–63. [Google Scholar]
  • 7.Schindler R, Mancilla J, Endres S, Ghorbani R, Clark SC, Dinarello CA. Correlations and interactions in the production of interleukin-6 (IL-6), IL-1, and tumor necrosis factor (TNF) in human mononuclear cells: IL-6 suppresses IL-1 and TNF. Blood. 1990;75:40–47. [PubMed] [Google Scholar]
  • 8.Li J, Perrella MA, Tsai JC, Yet SF, Hsieh CM, Yoshizumi M, Patterson C, Endege WO, Zhou F, Lee ME. Induction of vascular endothelial growth factor gene expression by interleukin-1β in rat aortic smooth muscle cells. J Biol Chem. 1995;270:308–312. doi: 10.1074/jbc.270.1.308. [DOI] [PubMed] [Google Scholar]
  • 9.Levitas E, Chamoun D, Udoff LC, et al. Periovulatory and interleukin (IL)-1 dependent upregulation of intraovarian vascular endothelial growth factor (VEGF): Potential role for VEGF in the promotion of periovulatory angiogenesis and vascular permeability. J Soc Gynecol Invest. 1997;4(Suppl):87. doi: 10.1016/s1071-5576(99)00066-0. [DOI] [PubMed] [Google Scholar]
  • 10.Cohen T, Nahari D, Cerem LW, Neufeld G, Levi BZ. Interleukin 6 induces the expression of vascular endothelial growth factor. J Biol Chem. 1996;271:736–741. doi: 10.1074/jbc.271.2.736. [DOI] [PubMed] [Google Scholar]
  • 11.Friedman C., Danforth DR, Herbosa-Encarnación C, Arbogast L, Alak BM, Seifer DB. Follicular fluid vascular endothelial growth factor concentrations are elevated in women of advanced reproductive age undergoing ovulation induction. Fertil Steril. 1997;68:607–612. doi: 10.1016/s0015-0282(97)00278-1. [DOI] [PubMed] [Google Scholar]
  • 12.Motro B, Itin A, Sachs L, Keshet E. Pattern of interleukin-6 gene expression in vivo suggests a role for this cytokine in angiogenesis. Proc Natl Acad Sci USA. 1990;87:3092–3096. doi: 10.1073/pnas.87.8.3092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Buyalos RP, Watson JM, Martinez-Maza O. Detection of interleukin-6 in human follicular fluid. Fertil Steril. 1992;57:1230–1234. [PubMed] [Google Scholar]
  • 14.Loret de Mola JR, Flores JP, Baumgardner GP, Goldfarb JM, Gindlesperger V, Friedlander MA. Elevated interleukin-6 levels in the ovarian hyperstimulation syndrome: Ovarian immunohistochemical localization of interleukin-6 signal. Obstet Gynecol. 1996;87:581–586. doi: 10.1016/0029-7844(95)00456-4. [DOI] [PubMed] [Google Scholar]
  • 15.Gaulden ME. Maternal age effect: The enigma of Down's syndrome and other trisomic conditions. Mutat Res. 1992;296:69–88. doi: 10.1016/0165-1110(92)90033-6. [DOI] [PubMed] [Google Scholar]
  • 16.Van Blerkom J, Antczak M, Schrader R. The developmental potential of the human oocyte is related to the dissolved oxygen content of follicular fluid: Association with vascular endothelial growth factor levels and perifollicular blood flow characteristics. Hum Reprod. 1997;12:1047–1055. doi: 10.1093/humrep/12.5.1047. [DOI] [PubMed] [Google Scholar]
  • 17.Plachot M, Veiga A, Montagut J, de Grouchy J, Calderon G, Lepretre S, Junca AM, Santalo J, Carles E, Mandelbaum J, et al. Are clinical and biological IVF parameters correlated with chromosomal disorders in early life: A multicentric study. Hum Reprod. 1988;3:627–635. doi: 10.1093/oxfordjournals.humrep.a136758. [DOI] [PubMed] [Google Scholar]
  • 18.Battaglia DE, Goodwin P, Klein NA, Soules MR. Influence of maternal age on meiotic spindle assembly in oocytes from naturally cycling women. Hum Reprod. 1996;11:2217–2222. doi: 10.1093/oxfordjournals.humrep.a019080. [DOI] [PubMed] [Google Scholar]
  • 19.Munné S, Alikani M, Tomkin G, Grifo J, Cohen J. Embryo morphology, developmental rates, and maternal age are correlated with chromosomal abnormalities. Fertil. Steril. 1995;64:382–391. [PubMed] [Google Scholar]
  • 20.Janny L, Menezo YJR. Maternal age effect on early human embryonic development and blastocyst formation. Mol Reprod Dev. 1996;45:31–37. doi: 10.1002/(SICI)1098-2795(199609)45:1<31::AID-MRD4>3.0.CO;2-T. [DOI] [PubMed] [Google Scholar]
  • 21.Friedlander MA, Loret de Mola JR, Goldfarb JM. Elevated levels of interleukin-6 in ascites and serum from women with ovarian hyperstimulation syndrome. Fertil Steril. 1993;60:826–833. doi: 10.1016/s0015-0282(16)56283-9. [DOI] [PubMed] [Google Scholar]
  • 22.Revel A, Barak V, Lavy Y, Anteby E, Abramov Y, Schenker JJ, Amit A, Finci-Yeheskel Z, Mayer M, Simon A, Laufer N, Hurwitz A. Characterization of intraperitoneal cytokines and nitrites in women with severe ovarian hyperstimulation syndrome. Fertil Steril. 1996;66:66–71. [PubMed] [Google Scholar]

Articles from Journal of Assisted Reproduction and Genetics are provided here courtesy of Springer Science+Business Media, LLC

RESOURCES