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

  • Reproductive Physiology and Disease
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

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.

Methods

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).

Results

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.

Conclusions

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.

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Acknowledgements

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.

Funding

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

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Authors and Affiliations

  1. Laboratory of Reproductive Biology, The Juliane Marie Centre for Women, Children and Reproduction, Rigshospitalet, Copenhagen University Hospital, Copenhagen University, DK-2100, Copenhagen, Denmark

    Jane Alrø Bøtkjær, Susanne Elisabeth Pors, Tonny Studsgaard Petersen, Stine Gry Kristensen, Janni Vikkelsø Jeppesen & Claus Yding Andersen

  2. Department of Molecular Biology and Genetics, University of Aarhus, DK-8000, Aarhus, Denmark

    Claus Oxvig

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  1. Jane Alrø Bøtkjær
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Additional gene expression profiles of IGF genes during human folliculogenesis (TIF 1.83 MB)

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Bøtkjær, J.A., Pors, S.E., Petersen, T.S. et al. Transcription profile of the insulin-like growth factor signaling pathway during human ovarian follicular development. J Assist Reprod Genet 36, 889–903 (2019). https://doi.org/10.1007/s10815-019-01432-x

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