Transcription profile of the insulin-like growth factor signaling pathway during human ovarian follicular development

  • Jane Alrø BøtkjærEmail author
  • Susanne Elisabeth Pors
  • Tonny Studsgaard Petersen
  • Stine Gry Kristensen
  • Janni Vikkelsø Jeppesen
  • Claus Oxvig
  • Claus Yding Andersen
Reproductive Physiology and Disease



The IGF signaling cascade exerts important regulatory functions in human ovarian folliculogenesis. The scope of this study was to evaluate the transcription profile of insulin-like growth factor (IGF) genes during human ovarian follicle development and to analyze follicle fluid levels of key IGF proteins.


Gene expression profiling was performed with microarray gene analysis. The analysis was assessed from ovarian follicles and granulosa cells (GCs) obtained from isolated stage-specific human ovarian follicles, including preantral follicles, small antral follicles, and preovulatory follicles. Numerous genes involved in the IGF signaling pathway was evaluated and key genes were validated by qPCR from GCs. Protein levels of various IGF components of human follicular fluid (FF) were measured by ELISA and time-resolved immunofluorometric assays (TRIFMA).


The gene expression levels of PAPPA, IGF2, IGF receptors and intracellular IGF-activated genes increased with increasing follicle size. This was especially prominent in the late preovulatory stage where IGF2 expression peaked. Protein levels of intact IGF binding protein-4 decreased significantly in FF from large preovulatory follicles compared with small antral follicles concomitant with higher protein levels of PAPP-A. The IGF modulators IGF-2 receptor, IGFBPs, stanniocalcins, and IGF-2 mRNA binding proteins were all observed to be expressed in the different follicle stages.


This study confirms and highlights the importance of PAPP-A regulating bioactive IGF levels throughout folliculogenesis and especially for the high rate of granulosa cell proliferation and expression of key ovarian hormones important in the last part of the follicular phase of the menstrual cycle.


IGF system IGFBPs PAPP-A Stanniocalcins Human ovarian follicles 



We acknowledge the Core Facility for helping with fine microarray analysis. Furthermore, we are thankful for the work performed at the fertility clinics in regard to collecting the granulosa cells and follicular fluids from IVF patients. Finally, we thank Pernille Rimmer Noer from the Department of Molecular Biology and Genetics at University of Aarhus for technical assistance.


The financial support from The Novo Nordisk Foundation, the Lundbeck Foundation, and Gangstedfonden is gratefully acknowledged.

Compliance with ethical standards

Conflict of interest

The authors declare no conflict of interest.

Supplementary material

10815_2019_1432_MOESM1_ESM.tif (1.8 mb)
ESM 1 Additional gene expression profiles of IGF genes during human folliculogenesis (TIF 1.83 MB)

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Copyright information

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

Authors and Affiliations

  • Jane Alrø Bøtkjær
    • 1
    Email author
  • Susanne Elisabeth Pors
    • 1
  • Tonny Studsgaard Petersen
    • 1
  • Stine Gry Kristensen
    • 1
  • Janni Vikkelsø Jeppesen
    • 1
  • Claus Oxvig
    • 2
  • Claus Yding Andersen
    • 1
  1. 1.Laboratory of Reproductive Biology, The Juliane Marie Centre for Women, Children and Reproduction, Rigshospitalet, Copenhagen University HospitalCopenhagen UniversityCopenhagenDenmark
  2. 2.Department of Molecular Biology and GeneticsUniversity of AarhusAarhusDenmark

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