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Pharmacological administration of recombinant human AMH rescues ovarian reserve and preserves fertility in a mouse model of chemotherapy, without interfering with anti-tumoural effects

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

Abstract

Purpose

To determine whether pharmacological administration of recombinant human anti-Mullerian hormone (rAMH) protects the ovarian reserve and preserves fertility without interfering with anti-tumoural cytotoxic action of chemotherapy.

Methods

Intraperitoneal delivery of rAMH and ovarian post-receptor activity were assessed with immunohistochemistry and western blot. Differential follicle counts and reproductive outcomes were assessed after cyclophosphamide (Cy) administration, with/without concurrent administration of rAMH. Interference of rAMH with Cy chemotoxicity was assessed on a human breast cancer cell line and an in vivo mouse model of human leukaemia.

Results

rAMH reached the ovary after intraperitoneal injection and demonstrated post-receptor bioactivity. Cy administration in mice caused primordial follicle activation, as shown by a decrease in primordial follicle population accompanied by an increase in early growing follicles and granulosa cell proliferation. Co-administration of rAMH reduced follicle activation, thereby protecting the primordial follicle reserve, and improving long-term fertility and reproductive outcomes. rAMH co-administration did not interfere with the cytotoxic actions of Cy in vitro on breast cancer cell line or in vivo in a model of human leukaemia.

Conclusion

This study demonstrates that rAMH is bioactive in the ovary for a limited time, and that pharmacological administration of rAMH during chemotherapy treatment reduces follicle activation and primordial follicle loss and significantly improves reproductive outcomes in a mouse model, and does not interfere with the therapeutic actions of the treatment. Further investigation is necessary to determine whether it has similar protective effects in the human ovary.

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Funding

This work was financially supported by grants from The Israel Innovation Authority (Grant No. 53789), and the Kahn Foundation.

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Authors and Affiliations

  1. Fertility Preservation Research Laboratory, Department of Obstetrics and Gynecology, Sheba Medical Centre, Ramat Gan, Israel

    H. Roness, I. Spector, Y. Leichtmann-Bardoogo, Sanaz Dereh-Haim & Dror Meirow

  2. Department of Human Molecular Genetics and Biochemistry, Sheba Medical Centre, Ramat Gan, Israel

    A. M. Savino

  3. Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

    Dror Meirow

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  1. H. Roness
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  2. I. Spector
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  3. Y. Leichtmann-Bardoogo
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  4. A. M. Savino
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  5. Sanaz Dereh-Haim
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  6. Dror Meirow
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Corresponding author

Correspondence to Dror Meirow.

Ethics declarations

All animal experiments were approved by the Institutional Animal Care and Use Ethics Committee.

Conflict of interest

D.M. and H.R. are holders of U.S. Provisional Patent Application No. 62/044,259, titled “Methods for preventing premature follicle activation.”

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Roness, H., Spector, I., Leichtmann-Bardoogo, Y. et al. Pharmacological administration of recombinant human AMH rescues ovarian reserve and preserves fertility in a mouse model of chemotherapy, without interfering with anti-tumoural effects. J Assist Reprod Genet 36, 1793–1803 (2019). https://doi.org/10.1007/s10815-019-01507-9

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  • DOI: https://doi.org/10.1007/s10815-019-01507-9

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