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Long-term imatinib diminishes ovarian reserve and impacts embryo quality

  • Fertility Preservation
  • Published:
Journal of Assisted Reproduction and Genetics Aims and scope Submit manuscript

Abstract

Purpose

Tyrosine kinase inhibitors (TKIs) such as imatinib are commonly used chemotherapeutics, but the effects of long-term treatments on reproductive outlook for cancer survivors are unknown. The purpose of this study was to examine the effects of long-term imatinib treatments on follicle development and embryo quality. Since prospective studies are not possible in healthy humans, we have incorporated a commonly used mouse model.

Methods

Adult female mice were treated with daily IP injections of imatinib for 4–6 weeks. Liquid chromatography-mass spectrometry was used to measure imatinib in serum and ovarian tissues. At the end of treatments, females were superovulated and mated to yield fertilized embryos. Oocytes and embryos were collected from oviducts, assessed for development by microscopy, and fertilized embryos were cultured in vitro. Blastocysts were fixed and stained for differential cell counts.

Results

Long-term imatinib treatments caused a shift in follicle development, with imatinib-treated females having fewer primordial follicles, but an increase in primary and secondary follicles (P < 0.05). There was no effect on ovulation or fertilization rates. However, blastocysts from imatinib-treated females had fewer total cells (P < 0.05) and a significant shift from inner cell mass to increased trophectoderm cells.

Conclusion

This pilot study indicates that long-term TKI treatments may have significant impact on ovarian reserve and embryo developmental capacity. More studies are needed in other model systems to determine the long-term impact of TKIs in patients. Knowing the potential effects of chemotherapeutics on reproductive outlook is critical for quality of life and more research is needed.

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Acknowledgments

A special thank you to Dr. Dennis Koop and Ms. Jenny Luo from the OHSU Bioanalytical Shared Resource/Pharmacokinetics Core for assistance with the LC-MS/MS analysis. The facility is part of the University Shared Resource Program supported by Oregon Health and Sciences University.

Funding

This research was supported by Grant No. IRG-58-007-54 from the American Cancer Society with pilot funding awarded to LKM; a fellowship research award from the Goldhirsh-Yellin Foundation to WS; and USC Norris Cancer Center Grant No. 2P30CA014089-43.

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Southern California, Los Angeles, CA, USA

    Wael Salem, Jacqueline R. Ho, Irene Woo, Karine Chung, Richard J. Paulson & Lynda K. McGinnis

  2. Department of Preventative Medicine, University of Southern California, Los Angeles, CA, USA

    Sue A. Ingles

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  1. Wael Salem
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  2. Jacqueline R. Ho
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  3. Irene Woo
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  5. Karine Chung
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  7. Lynda K. McGinnis
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Contributions

All authors were involved in the initial planning of the research, reviewing frequent updates on the research progress, reviewing the data results, and writing the manuscript. LKM and WS treated the animals; LKM and IW conducted the cultures; WS counted follicles; LKM graded embryo development and counted blastocyst cells; SAI reviewed study designs and conducted the statistical analysis; IW, WA, and LKM drafted the manuscript; JRH, KC, and RJP reviewed all of the proposed research, critically evaluated the data, and contributed to the writing of the manuscript.

Corresponding author

Correspondence to Lynda K. McGinnis.

Ethics declarations

All experiments were conducted in accordance with the “Guide for the Care and use of laboratory Animals” and preapproved by the University of Southern California Institutional Animal Care and Use Committee.

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Salem, W., Ho, J.R., Woo, I. et al. Long-term imatinib diminishes ovarian reserve and impacts embryo quality. J Assist Reprod Genet 37, 1459–1466 (2020). https://doi.org/10.1007/s10815-020-01778-7

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  • DOI: https://doi.org/10.1007/s10815-020-01778-7

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