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Follicle activation is a significant and immediate cause of follicle loss after ovarian tissue transplantation

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

Abstract

Purpose

Extensive follicle loss has been demonstrated in ovarian grafts post transplantation, reducing their productivity and lifespan. Several mechanisms for this loss have been proposed, and this study aims to clarify when and how the massive follicle loss associated with transplantation of ovarian tissue graft occurs. An understanding of the mechanisms of follicle loss will pinpoint potential new targets for optimization and improvement of this important fertility preservation technique.

Methods

Frozen-thawed marmoset (n = 15), bovine (n = 37), and human (n = 46) ovarian cortical tissue strips were transplanted subcutaneously into immunodeficient castrated male mice for 3 or 7 days. Histological (H&E, Masson’s trichrome) analysis and immunostaining (Ki-67, GDF9, cleaved caspase-3) were conducted to assess transplantation-associated follicle dynamics, with untransplanted frozen-thawed tissue serving as a negative control.

Results

Evidence of extensive primordial follicle (PMF) activation and loss was observed already 3 days post transplantation in marmoset, bovine, and human tissue grafts, compared to frozen-thawed untransplanted controls (p < 0.001). No significant additional PMF loss was observed 7 days post transplantation. Recovered grafts of all species showed markedly higher rates of proliferative activity and progression from dormant to growing follicles (Ki-67 and GDF9 staining) as well as higher growing/primordial (GF/PMF) ratio (p < 0.02) and higher collagen levels compared with untransplanted controls.

Conclusions

This multi-species study demonstrates that follicle activation plays an important role in transplantation-induced follicle loss, and that it occurs within a very short time frame after grafting. These results underline the need to prevent this activation at the time of transplantation in order to retain the maximal possible follicle reserve and extend graft lifespan.

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Acknowledgements

The authors wish to thank Mrs. Sanaz Dereh-Haim, Mrs. Reinhild Sandhowe-Klawerkamp, and Mr. Martin Heuermann for excellent technical assistance and animal care. The following foundations contributed to the funding of this study: Israel Science Foundation and Kahn Foundation.

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Authors and Affiliations

  1. Fertility Preservation Laboratory, Sheba Medical Center, Tel Hashomer, Israel

    Zohar Gavish, Itay Spector, Hadassa Roness & Dror Meirow

  2. IVF Division, Carmel Medical Center, the Ruth & Bruce Rappaport Faculty of Medicine, Technion Institute of Technology, Haifa, Israel

    Gil Peer

  3. Centre of Reproductive Medicine and Andrology, Institute of Reproductive and Regenerative Biology, Muenster, Germany

    Stefan Schlatt & Joachim Wistuba

  4. Sackler School of Medicine, Tel Aviv University, P.O. Box 39040, 6997801, Tel Aviv, Israel

    Dror Meirow

Authors
  1. Zohar Gavish
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  2. Itay Spector
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  3. Gil Peer
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  4. Stefan Schlatt
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  5. Joachim Wistuba
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  6. Hadassa Roness
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  7. Dror Meirow
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Corresponding author

Correspondence to Dror Meirow.

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All procedures were conducted according to the German Law on the Care and Use of Laboratory Animals under license 84-02.05.20.12.0.018.

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Gavish, Z., Spector, I., Peer, G. et al. Follicle activation is a significant and immediate cause of follicle loss after ovarian tissue transplantation. J Assist Reprod Genet 35, 61–69 (2018). https://doi.org/10.1007/s10815-017-1079-z

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  • DOI: https://doi.org/10.1007/s10815-017-1079-z

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