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      Cancer treatment in childhood and testicular function: the importance of the somatic environment

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          Abstract

          Testicular function and future fertility may be affected by cancer treatment during childhood. Whilst survival of the germ (stem) cells is critical for ensuring the potential for fertility in these patients, the somatic cell populations also play a crucial role in providing a suitable environment to support germ cell maintenance and subsequent development. Regulation of the spermatogonial germ-stem cell niche involves many signalling pathways with hormonal influence from the hypothalamo-pituitary-gonadal axis. In this review, we describe the somatic cell populations that comprise the testicular germ-stem cell niche in humans and how they may be affected by cancer treatment during childhood. We also discuss the experimental models that may be utilized to manipulate the somatic environment and report the results of studies that investigate the potential role of somatic cells in the protection of the germ cells in the testis from cancer treatment.

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          Most cited references 136

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          Spermatogonial stem cell transplantation into rhesus testes regenerates spermatogenesis producing functional sperm.

          Spermatogonial stem cells (SSCs) maintain spermatogenesis throughout a man's life and may have application for treating some cases of male infertility, including those caused by chemotherapy before puberty. We performed autologous and allogeneic SSC transplantations into the testes of 18 adult and 5 prepubertal recipient macaques that were rendered infertile with alkylating chemotherapy. After autologous transplant, the donor genotype from lentivirus-marked SSCs was evident in the ejaculated sperm of 9/12 adult and 3/5 prepubertal recipients after they reached maturity. Allogeneic transplant led to donor-recipient chimerism in sperm from 2/6 adult recipients. Ejaculated sperm from one recipient transplanted with allogeneic donor SSCs were injected into 85 rhesus oocytes via intracytoplasmic sperm injection. Eighty-one oocytes were fertilized, producing embryos ranging from four-cell to blastocyst with donor paternal origin confirmed in 7/81 embryos. This demonstration of functional donor spermatogenesis following SSC transplantation in primates is an important milestone for informed clinical translation. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Retinoic acid, meiosis and germ cell fate in mammals.

            Although mammalian sex is determined genetically, the sex-specific development of germ cells as sperm or oocytes is initiated by cues provided by the gonadal environment. During embryogenesis, germ cells in an ovary enter meiosis, thereby committing to oogenesis. By contrast, germ cells in a testicular environment do not enter meiosis until puberty. Recent findings indicate that the key to this sex-specific timing of meiosis entry is the presence or absence of the signaling molecule retinoic acid. Although this knowledge clarifies a long-standing mystery in reproductive biology, it also poses many new questions, which we discuss in this review.
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              A European perspective on testicular tissue cryopreservation for fertility preservation in prepubertal and adolescent boys.

              What clinical practices, patient management strategies and experimental methods are currently being used to preserve and restore the fertility of prepubertal boys and adolescent males?
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                Author and article information

                Journal
                Endocr Connect
                Endocr Connect
                EC
                Endocrine Connections
                Bioscientifica Ltd (Bristol )
                2049-3614
                February 2018
                19 January 2018
                : 7
                : 2
                : R69-R87
                Affiliations
                [1 ]NORDFERTIL Research Lab Stockholm Pediatric Endocrinology Unit, Department of Women’s and Children’s Health, Karolinska Institutet and University Hospital, Stockholm, Sweden
                [2 ]Division of Haematology-Oncology and Stem Cell Transplantation Children’s Hospital, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland
                [3 ]MRC Centre for Reproductive Health The Queen’s Medical Research Institute, The University of Edinburgh, Edinburgh, UK
                [4 ]Edinburgh Royal Hospital for Sick Children Edinburgh, UK
                Author notes
                Correspondence should be addressed to R Mitchell: rod.mitchell@ 123456ed.ac.uk

                *(J-B Stukenborg and K Jahnukainen contributed equally to this work)

                Article
                EC170382
                10.1530/EC-17-0382
                5817964
                29351905
                © 2018 The authors

                This work is licensed under a Creative Commons Attribution 4.0 International License.

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