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

doi:10.1530/EC-17-0382

Review

. 2018 Feb;7(2):R69-R87.

doi: 10.1530/EC-17-0382. Epub 2018 Jan 19.

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

Jan-Bernd Stukenborg¹, Kirsi Jahnukainen^{1

2}, Marsida Hutka³, Rod T Mitchell^{4

5}

Affiliations

¹ NORDFERTIL Research Lab StockholmPediatric 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 TransplantationChildren's Hospital, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland.
³ MRC Centre for Reproductive HealthThe Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
⁴ MRC Centre for Reproductive HealthThe Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK rod.mitchell@ed.ac.uk.
⁵ Edinburgh Royal Hospital for Sick ChildrenEdinburgh, UK.

PMID: 29351905
PMCID: PMC5817964
DOI: 10.1530/EC-17-0382

Review

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

Jan-Bernd Stukenborg et al. Endocr Connect. 2018 Feb.

. 2018 Feb;7(2):R69-R87.

doi: 10.1530/EC-17-0382. Epub 2018 Jan 19.

Authors

Jan-Bernd Stukenborg¹, Kirsi Jahnukainen^{1

2}, Marsida Hutka³, Rod T Mitchell^{4

5}

Affiliations

¹ NORDFERTIL Research Lab StockholmPediatric 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 TransplantationChildren's Hospital, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland.
³ MRC Centre for Reproductive HealthThe Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK.
⁴ MRC Centre for Reproductive HealthThe Queen's Medical Research Institute, The University of Edinburgh, Edinburgh, UK rod.mitchell@ed.ac.uk.
⁵ Edinburgh Royal Hospital for Sick ChildrenEdinburgh, UK.

PMID: 29351905
PMCID: PMC5817964
DOI: 10.1530/EC-17-0382

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.

Keywords: cancer treatment; fertility; fertility preservation; testis.

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Figures

**Figure 1**
Sertoli and Leydig cell development and profile of reproductive hormone secretion in humans from birth to adulthood. Sertoli cell maturation involves changes in morphology, protein expression (including AMH and AR) and proliferation, whilst Leydig cell development involves two distinct populations of cells, which include a foetal Leydig cell population which regresses postnatally to be replaced by an adult Leydig cell population derived from a precursor population present in the prepubertal testis. Relative hormone production based on data taken from normal human populations (19, 20, 21). Whilst gonadotrophins are undetectable during childhood, Sertoli cell-derived hormones Inhibin B and AMH remain detectable.

**Figure 2**
Cellular targets for chemotherapy and/or radiotherapy-induced damage in the prepubertal testis. Infertility may result from damage within the seminiferous tubules as a result of direct damage to the spermatogonia leading to alterations in proliferation, differentiation, protein deamination and apoptosis and ultimately infertility. Alternatively, damage to the Sertoli cells by such treatments may result in alterations in hormones, growth factors or seminiferous tubule structure that will indirectly mediate the effects of chemo/radiotherapy on the germ cells. Similarly, interstitial effects include damage to the Leydig cells that can lead to alterations in hormones or growth factors that may impact germ cells directly or indirectly (e.g. testosterone deficiency) through effects other somatic cell populations.

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References

1. Yoshida S, Sukeno M, Nabeshima Y. A vasculature-associated niche for undifferentiated spermatogonia in the mouse testis. Science 2007. 317 1722–1726. (10.1126/science.1144885) - DOI - PubMed
1. Oatley JM, Brinster RL. The germline stem cell niche unit in mammalian testes. Physiological Reviews 2012. 92 577–595. (10.1152/physrev.00025.2011) - DOI - PMC - PubMed
1. Chen SR, Liu YX. Regulation of spermatogonial stem cell self-renewal and spermatocyte meiosis by Sertoli cell signaling. Reproduction 2015. 149 R159–R167. (10.1530/REP-14-0481) - DOI - PubMed
1. Jahnukainen K, Mitchell RT, Stukenborg JB. Testicular function and fertility preservation after treatment for haematological cancer. Current Opinion in Endocrinology, Diabetes and Obesity 2015. 22 217–223. (10.1097/MED.0000000000000156) - DOI - PubMed
1. Anderson RA, Mitchell RT, Kelsey TW, Spears N, Telfer EE, Wallace WH. Cancer treatment and gonadal function: experimental and established strategies for fertility preservation in children and young adults. Lancet Diabetes and Endocrinology 2015. 3 556–567. (10.1016/S2213-8587(15)00039-X) - DOI - PubMed

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[1] Yoshida S, Sukeno M, Nabeshima Y. A vasculature-associated niche for undifferentiated spermatogonia in the mouse testis. Science 2007. 317 1722–1726. (10.1126/science.1144885) - DOI - PubMed

[2] Yoshida S, Sukeno M, Nabeshima Y. A vasculature-associated niche for undifferentiated spermatogonia in the mouse testis. Science 2007. 317 1722–1726. (10.1126/science.1144885) - DOI - PubMed

[3] Oatley JM, Brinster RL. The germline stem cell niche unit in mammalian testes. Physiological Reviews 2012. 92 577–595. (10.1152/physrev.00025.2011) - DOI - PMC - PubMed

[4] Oatley JM, Brinster RL. The germline stem cell niche unit in mammalian testes. Physiological Reviews 2012. 92 577–595. (10.1152/physrev.00025.2011) - DOI - PMC - PubMed

[5] Chen SR, Liu YX. Regulation of spermatogonial stem cell self-renewal and spermatocyte meiosis by Sertoli cell signaling. Reproduction 2015. 149 R159–R167. (10.1530/REP-14-0481) - DOI - PubMed

[6] Chen SR, Liu YX. Regulation of spermatogonial stem cell self-renewal and spermatocyte meiosis by Sertoli cell signaling. Reproduction 2015. 149 R159–R167. (10.1530/REP-14-0481) - DOI - PubMed

[7] Jahnukainen K, Mitchell RT, Stukenborg JB. Testicular function and fertility preservation after treatment for haematological cancer. Current Opinion in Endocrinology, Diabetes and Obesity 2015. 22 217–223. (10.1097/MED.0000000000000156) - DOI - PubMed

[8] Jahnukainen K, Mitchell RT, Stukenborg JB. Testicular function and fertility preservation after treatment for haematological cancer. Current Opinion in Endocrinology, Diabetes and Obesity 2015. 22 217–223. (10.1097/MED.0000000000000156) - DOI - PubMed

[9] Anderson RA, Mitchell RT, Kelsey TW, Spears N, Telfer EE, Wallace WH. Cancer treatment and gonadal function: experimental and established strategies for fertility preservation in children and young adults. Lancet Diabetes and Endocrinology 2015. 3 556–567. (10.1016/S2213-8587(15)00039-X) - DOI - PubMed

[10] Anderson RA, Mitchell RT, Kelsey TW, Spears N, Telfer EE, Wallace WH. Cancer treatment and gonadal function: experimental and established strategies for fertility preservation in children and young adults. Lancet Diabetes and Endocrinology 2015. 3 556–567. (10.1016/S2213-8587(15)00039-X) - DOI - PubMed

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

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

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