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Open AccessArticle

Fertility Preservation in Childhood Cancer: Endocrine Activity in Prepubertal Human Testis Xenografts Exposed to a Pubertal Hormone Environment

1
Medical Research Council (MRC) Centre for Reproductive Health, The University of Edinburgh, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
2
Biology of the Testis, Research Laboratory for Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel (VUB), Laarbeeklaan 103, 1090 Brussels, Belgium
3
Edinburgh CRF Mass Spectrometry Core, Centre for Cardiovascular Science, The University of Edinburgh, The Queen’s Medical Research Institute, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
4
Department of Oncology and Haematology, Royal Hospital for Sick Children, 9 Sciennes Road, Edinburgh EH9 1LF, UK
5
School of Environmental and Life Sciences, University of Newcastle, Callaghan, 2308 New South Wales, Australia
6
NORDFERTIL Research Lab Stockholm, Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, and Karolinska University Hospital, Visionsgatan 4, 171 64 Solna, Sweden
7
Department of Diabetes and Endocrinology, Royal Hospital for Sick Children, 9 Sciennes Road, Edinburgh EH9 1LF, UK
*
Author to whom correspondence should be addressed.
Cancers 2020, 12(10), 2830; https://doi.org/10.3390/cancers12102830
Received: 21 July 2020 / Revised: 23 September 2020 / Accepted: 24 September 2020 / Published: 30 September 2020
(This article belongs to the Special Issue Efforts to Mitigate the Toxicity of Cancer Therapeutics)
Substantial strides have been made in treating childhood cancers; however, as a result of chemotherapy and radiotherapy, young males experience long-term side effects, including impaired fertility. Whilst prepubertal testicular tissue can be cryopreserved prior to gonadotoxic treatments, it remains to be determined how to generate mature gametes from the immature human testis tissue. Development of immature germ cells into sperm is a complex process, which is supported by mature Sertoli cells and testosterone produced from Leydig cells. We used an established testicular xenotransplantation model to investigate the effect of puberty hormones, known as gonadotrophins, on functional maturation of the spermatogonial stem cell (SSC) niche. Limited testosterone production and partial maturation of Sertoli cells occurred in prepubertal testis grafts, suggesting that longer periods of grafting and/or identification of additional factors are required to develop testicular transplantation as a model for fertility preservation in male survivors of childhood cancer.
Survivors of childhood cancer are at risk for long-term treatment-induced health sequelae, including gonadotoxicity and iatrogenic infertility. At present, for prepubertal boys there are no viable clinical options to preserve future reproductive potential. We investigated the effect of a pubertal induction regimen with gonadotrophins on prepubertal human testis xenograft development. Human testis tissue was obtained from patients with cancer and non-malignant haematological disorders (n = 6; aged 1–14 years) who underwent testis tissue cryopreservation for fertility preservation. Fresh and frozen-thawed testis fragments were transplanted subcutaneously or intratesticularly into immunocompromised mice. Graft-bearing mice received injections of vehicle or exogenous gonadotrophins, human chorionic gonadotrophin (hCG, 20 IU), and follicle-stimulating hormone (FSH, 12.5 IU) three times a week for 12 weeks. The gross morphology of vehicle and gonadotrophin-exposed grafts was similar for both transplantation sites. Exposure of prepubertal human testis tissue xenografts to exogenous gonadotrophins resulted in limited endocrine function of grafts, as demonstrated by the occasional expression of the steroidogenic cholesterol side-chain cleavage enzyme (CYP11A1). Plasma testosterone concentrations (0.13 vs. 0.25 ng/mL; p = 0.594) and seminal vesicle weights (10.02 vs. 13.93 mg; p = 0.431) in gonadotrophin-exposed recipient mice were comparable to vehicle-exposed controls. Regardless of the transplantation site and treatment, initiation and maintenance of androgen receptor (AR) expression were observed in Sertoli cells, indicating commitment towards a more differentiated status. However, neither exogenous gonadotrophins (in castrated host mice) nor endogenous testosterone (in intact host mice) were sufficient to repress the expression of markers associated with immature Sertoli cells, such as anti-Müllerian hormone (AMH) and Ki67, or to induce the redistribution of junctional proteins (connexin 43, CX43; claudin 11, CLDN11) to areas adjacent to the basement membrane. Spermatogonia did not progress developmentally but remained the most advanced germ cell type in testis xenografts. Overall, these findings demonstrate that exogenous gonadotrophins promote partial activation and maturation of the somatic environment in prepubertal testis xenografts. However, alternative hormone regimens or additional factors for pubertal induction are required to complete the functional maturation of the spermatogonial stem cell (SSC) niche. View Full-Text
Keywords: prepubertal human testis; childhood cancer; gonadotoxicity; side effects; steroidogenesis; testosterone; hCG; FSH; fertility preservation; xenotransplantation prepubertal human testis; childhood cancer; gonadotoxicity; side effects; steroidogenesis; testosterone; hCG; FSH; fertility preservation; xenotransplantation
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MDPI and ACS Style

Hutka, M.; Kadam, P.; Van Saen, D.; Homer, N.Z.M.; Onofre, J.; Wallace, W.H.B.; Smith, L.B.; Stukenborg, J.-B.; Goossens, E.; Mitchell, R.T. Fertility Preservation in Childhood Cancer: Endocrine Activity in Prepubertal Human Testis Xenografts Exposed to a Pubertal Hormone Environment. Cancers 2020, 12, 2830. https://doi.org/10.3390/cancers12102830

AMA Style

Hutka M, Kadam P, Van Saen D, Homer NZM, Onofre J, Wallace WHB, Smith LB, Stukenborg J-B, Goossens E, Mitchell RT. Fertility Preservation in Childhood Cancer: Endocrine Activity in Prepubertal Human Testis Xenografts Exposed to a Pubertal Hormone Environment. Cancers. 2020; 12(10):2830. https://doi.org/10.3390/cancers12102830

Chicago/Turabian Style

Hutka, Marsida; Kadam, Prashant; Van Saen, Dorien; Homer, Natalie Z.M.; Onofre, Jaime; Wallace, W. H.B.; Smith, Lee B.; Stukenborg, Jan-Bernd; Goossens, Ellen; Mitchell, Rod T. 2020. "Fertility Preservation in Childhood Cancer: Endocrine Activity in Prepubertal Human Testis Xenografts Exposed to a Pubertal Hormone Environment" Cancers 12, no. 10: 2830. https://doi.org/10.3390/cancers12102830

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