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Modulation of the IGF system and proliferation in human endometrial stromal cells by metformin: a dose-dependent effect

  • Gynecologic Endocrinology and Reproductive Medicine
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Purpose

To assess the metformin effect on endometrial stromal cell decidualization, proliferation, gene and protein expression of IGFBPs, IGFs and their receptors.

Methods

Human endometrial stromal cells (hESCs) were cultured from endometrial biopsies of 11 women undergoing surgery for benign reasons. hESCs were decidualized with and without metformin in increasing doses. Supernatant and cells were harvested after decidualization for 12–14 days, followed by real-time PCR of IGFBP 1-6, IGF I, IGF II and their receptors. Prolactin, and IGFBP-1, -3, and -6 were additionally analyzed in supernatant by ELISA. Proliferation of hESCs and decidualization of hESCs were assessed under the influence of metformin. Data were analyzed using the paired t test with p < 0.05 considered significant.

Results

While lower concentrations of metformin (10−4, 10−5 M) did not influence the decidualization and proliferation capacity of hESCs, higher concentrations (10−3, 10−2 M metformin) significantly (p < 0.05) diminished decidualization, as well as stromal cell proliferation in a dose-dependent manner. Higher concentrations of metformin lead to a significant (p < 0.05) dose-dependent attenuation of the progesterone effect with regard to IGFBP-1, -3, -5, -6, as well as IGF I receptor, while it did not change the expression of IGFBP-2 and -4, IGF I and II and the IGF II receptor. This was confirmed on the protein level for IGFBP-1, -3, and -6.

Conclusion

We were able to demonstrate for the first time a dose-dependent local effect of metformin within hESCs. Metformin might therefore influence locally the endometrial proliferation and maturation, and could open up new treatment options for gynecological diseases by vaginal application of metformin.

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Acknowledgments

Edison Capp is scholarship recipient from Conselho Nacional de Desenvolvimento Científico e Tecnológico–CNPq, Brazil.

Conflict of interest

The authors have no conflict of interest.

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Author notes

    Authors and Affiliations

    1. Department of Gynecological Endocrinology and Reproductive Medicine, Ruprecht-Karls-University Heidelberg, Heidelberg, Germany

      Marie-Luise Jung, Tobias Renke, Julia Jauckus, Edison Capp, Thomas Strowitzki & Ariane Germeyer

    2. Department of Obstetrics and Gynecology Schwetzingen, Schwetzingen, Germany

      Oliver Nowak

    3. Central Laboratory Ruprecht-Karls-University Heidelberg, Heidelberg, Germany

      Markus Zorn

    4. Department of Obstetrics and Gynecology, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil

      Edison Capp

    5. Department of Gynecological Endocrinology and Reproductive Medicine, University Hospital Heidelberg, INF 440, 69210, Heidelberg, Germany

      Edison Capp & Ariane Germeyer

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    1. Marie-Luise Jung
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    Correspondence to Ariane Germeyer.

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    M.-L. Jung and T. Renke contributed equally.

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    Jung, ML., Renke, T., Nowak, O. et al. Modulation of the IGF system and proliferation in human endometrial stromal cells by metformin: a dose-dependent effect. Arch Gynecol Obstet 292, 465–472 (2015). https://doi.org/10.1007/s00404-015-3650-0

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    • DOI: https://doi.org/10.1007/s00404-015-3650-0

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