Insulin-like growth factor-1 and soluble FMS-like tyrosine kinase-1 prospectively predict cancelled IVF cycles

  • Dimitrios Nasioudis
  • Evelyn Minis
  • Mohamad Irani
  • Fabiana Kreines
  • Steven S. Witkin
  • Steven D. SpandorferEmail author
Assisted Reproduction Technologies



To identify biomarkers that prospectively predict IVF cycle cancellation.


In this prospective study, sera were obtained prior to any intervention, from women about to undergo an IVF cycle. The sera were assayed by ELISA for levels of insulin-like growth factor (IGF)-1, IGF-2, IGF binding protein (BP)-1, and soluble fms-like tyrosine kinase (sFLT-1). The cancellation or progression of the IVF cycle was subsequently obtained by chart review. Associations between serum components and outcome were analyzed by the Mann-Whitney test. Receiver operator curves were constructed to evaluate the strength of the correlations between biomarkers and cycle cancellation, as assessed from the area under the curve (AUC).


A total of 205 women were included. Twenty-seven (13.2%) cycle cancellations due to poor response were recorded. Women with a cancelled cycle had reduced anti-Mullerian hormone (AMH) values (p < 0.001) and antral follicle count (p = 0.003). There were no significant differences between the two groups with regard to age and BMI. Median concentrations of IGF-1 and sFLT-1 were elevated in sera from women whose IVF cycles were cancelled as compared to those with ongoing cycles (p = 0.015 and p < 0.001, respectively); AUC for IGF-1 and sFLT-1 were 0.67 and 0.75, respectively. Concentrations of sFLT-1 remained significantly higher in patients with cancelled cycles even after controlling for AMH levels. There were no differences in IGF-2 and IGFBP-1 levels between the two groups.


Measurement of circulating IGF-1 and sFLT-1 levels prior to initiation of an IVF cycle has the potential to identify women whose cycles have an increased likelihood to be subsequently cancelled.


Cycle cancellation IGF-1 sFLT-1 


Compliance with ethical standards

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 and/or national research committee (include name of committee + reference number) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.”

Informed consent

“Informed consent was obtained from all individual participants included in the study.”


  1. 1.
    Badawy A, Wageah A, El Gharib M, Osman EE. Prediction and diagnosis of poor ovarian response: the dilemma. J Reprod Infertil. 2011;12(4):241–8.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Garcia JE, Jones GS, Acosta AA, Wright G. Human menopausal gonadotropin/human chorionic gonadotropin follicular maturation for oocyte aspiration: phase I, 1981. Fertil Steril. 1983;39:167–73.CrossRefGoogle Scholar
  3. 3.
    Muasher SJ, Oehninger S, Simonetti S, Matta J, Ellis LM, Liu HC, et al. The value of basal and/or stimulated serum gonadotropin levels in prediction of stimulation response and in vitro fertilization outcome. Fertil Steril. 1988;50:298–307.CrossRefGoogle Scholar
  4. 4.
    Sharif K, Elgendy M, Lashen H, Afnan M. Age and basal follicle stimulating hormone as predictors of in vitro fertilisation outcome. Br J Obstet Gynaecol. 1998;105:107–12.CrossRefGoogle Scholar
  5. 5.
    Chuang CC, Chen CD, Chao KH, Chen SU, Ho HN, Yang YS. Age is a better predictor of pregnancy potential than basal follicle-stimulating hormone levels in women undergoing in vitro fertilization. Fertil Steril. 2003;79:63–8.CrossRefGoogle Scholar
  6. 6.
    Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update. 2006;12(6):685–718.CrossRefGoogle Scholar
  7. 7.
    Sills ES, Alper MM, Walsh AP. Ovarian reserve screening in infertility: practical applications and theoretical directions for research. Eur J Obstet Gynecol Reprod Biol. 2009;146(1):30–6. Scholar
  8. 8.
    La Marca A, Sunkara SK. Individualization of controlled ovarian stimulation in IVF using ovarian reserve markers: from theory to practice. Hum Reprod Update. 2014;1:124–40.CrossRefGoogle Scholar
  9. 9.
    Broekmans FJ, Kwee J, Hendriks DJ, Mol BW, Lambalk CB. A systematic review of tests predicting ovarian reserve and IVF outcome. Hum Reprod Update. 2006;6:685–718.CrossRefGoogle Scholar
  10. 10.
    Oosterhuis GJE, Vermes I, Lambalk CB, Michegelsen HWB, Shoemaker J. Insulin-like growth (IGF)-I and IGF binding protein-3 concentration in fluid from human stimulated follicles. Hum Reprod. 1998;13:285–9.CrossRefGoogle Scholar
  11. 11.
    Dor J, Ben-Shlomo I, Lunenfeld B. Insulin-like growth factor-I (IGF-I) may not be essential for ovarian follicular development: evidence from IGF-I deficiency. J Clin Endocrinol Metab. 1992;74:539–42.PubMedGoogle Scholar
  12. 12.
    Schoyer KD, Liu HC, Witkin S, Rosenwacks Z, Spandorfer SD. Serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3) in IVF patients with polycystic ovary syndrome: correlations with outcome. Fertil Steril. 2007;88:139–44.CrossRefGoogle Scholar
  13. 13.
    Choi YS, Kim SH, Ki SY, et al. Efficacy of ER-alpha polymorphisms and the intrafollicular IGF system for predicting pregnancy in IVF-ET patients. Gynecol Obstet Invest. 2009;67:73–80.CrossRefGoogle Scholar
  14. 14.
    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.CrossRefGoogle Scholar
  15. 15.
    Dorn C, Reinsberg J, Kupka M, van der Ven H, Schild RL. Leptin, VEGF, IGF-1 and IGFBP-3 concentrations in serum and follicular fluid of women undergoing in vitro fertilization. Arch Gynecol Obstet. 2003;268:187–93.CrossRefGoogle Scholar
  16. 16.
    Ramer I, Kanninen TT, Sisti G, Witkin SS, Spandorfer SD. Association of in vitro fertilization outcome with circulating insulin-like growth factor components prior to cycle initiation. Am J Obstet Gynecol. 2015;213:356.e1–6.CrossRefGoogle Scholar
  17. 17.
    Han VKM, Bassett N, Walton J, Challis JRG. The expression of insulin-like growth factor (IGF) and IGF binding protein (IGFBP) genes in the human placenta and membranes: evidence for IGF-IGFBP interactions at the feto-maternal interface. J Clin Endocrinol Metab. 1996;81:2680–93.PubMedGoogle Scholar
  18. 18.
    Pringle KG, Roberts CT. New light on early post-implantation pregnancy in the mouse: roles for insulin-like growth factor-II (IGF II)? Placenta. 2006;28:286–97.CrossRefGoogle Scholar
  19. 19.
    Irving JA, Lala PK. Cell surface integrins on human trophoblast cell migration: regulation by TGF-beta, IGF-II, and IGFBP-1. Exp Cell Res. 1995;217:419–27.CrossRefGoogle Scholar
  20. 20.
    Irwin JC, Giudice LC. Insulin-like growth factor binding protein-1 binds to placental cytotrophoblast a5b1 integrin and inhibits cytotrophoblast invasion into decidualized endometrial stromal cultures. Growth Horm IGF Res. 1998;8:21–31.CrossRefGoogle Scholar
  21. 21.
    Kawano Y, Narahara H, Matsui N, Nasu K, Miyamura K, Miyakawa I. Insulin-like growth factor-binding protein-1 in human follicular fluid: a marker of oocyte maturation. Gynecol Obstet Invest. 1997;44:145–8.CrossRefGoogle Scholar
  22. 22.
    Gutman G, Barak V, Maslovitz S, Amit A, Lessing JB, Geva E. Regulation of vascular endothelial factor-A and its soluble receptor sFLT-1 by luteinizing hormone in vivo: Implication for ovarian follicle angiogenesis. Fertil Steril. 2008;89:922–6.CrossRefGoogle Scholar
  23. 23.
    Vural F, Vural B, Doger E, Cakiroglu Y, Cekmen M. Perifollicular blood flow and its relationship with endometrial vascularity, follicular fluid EG-VEGF, IGF-1, and inhibin-a levels and IVF outcomes. J Assist Reprod Genet. 2016;33:1355–62.CrossRefGoogle Scholar
  24. 24.
    Davoren JB, Kasson BG, Li CH, Hsueh AJW. Specific insulin-like growth factor I– and II–binding sites on rat granulosa cells: relation to IGF action. Endocrinology. 1986;119:2155–62.CrossRefGoogle Scholar
  25. 25.
    Adashi EY. The ovarian follicle: life cycle of a pelvic clock. In: Adashi EY, Rock JA, Rosenwaks Z, editors. Reproductive endocrinology, surgery, and technology, vol. 1. Philadelphia: Lippincott-Raven; 1996. p. 211–34.Google Scholar
  26. 26.
    Davoren JB, Hsueh AJW, Li CH. Somatomedin C augments FSH-induced differentiation of cultured rat granulose cells. Am J Physiol. 1985;249:E26–33.PubMedGoogle Scholar
  27. 27.
    Adashi EY, Resnick CE, D’Ercole AJ, Svoboda ME, Van Wyk JJ. Insulin-like growth factors as intraovarian regulators of granulosa cell growth and function. Endocr Rev. 1985;6:400–20.CrossRefGoogle Scholar
  28. 28.
    Chun SY, Billig H, Tilly JL, Furuta I, Tsafriri A, Hsue AJ. Gonadotropin suppression of apoptosis in cultured preovulatory follicles: mediatory role of endogenous insulin-like growth factor I. Endocrinology. 1994;135:1845–53.CrossRefGoogle Scholar
  29. 29.
    Eden JA, Jones J, Carter GD, Alaghband-Zadeh J. A comparison of follicular fluid levels of insulin-like growth factor-1 in normal dominant and cohort follicles, polycystic and multicystic ovaries. Clin Endocrinol. 1988;29:327–36.CrossRefGoogle Scholar
  30. 30.
    Rabinovici J, Dandekar P, Angle MJ, Rosenthal S, Martin MC. Insulin like growth factor I (IGF-I) levels in follicular fluid from human revelatory follicles: correlation with serum IGF-I levels. Fertil Steril. 1990;54:428–33.CrossRefGoogle Scholar
  31. 31.
    Huang JY, Rosenwaks Z. Assisted reproductive techniques. Methods Mol Biol. 2014;1154:171–231.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Hospital of the University of PennsylvaniaHelen O’Dickens Women’s Health CenterPhiladelphiaUSA
  2. 2.Weill Cornell MedicineNew YorkUSA
  3. 3.Ronald O. Perelman and Claudia Cohen Center for Reproductive MedicineWeill Cornell MedicineYorkUSA

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