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Fertility Preservation for Children Treated for Cancer

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Fertility Preservation for Children Treated for Cancer Arch Dis Child 2001;84:355–359 355 PERSONAL PRACTICE Arch Dis Child: first published as 10.1136/adc.84.4.355 on 1 April 2001. Downloaded from Fertility preservation for children treated for cancer (1): scientific advances and research dilemmas Institute of Child Health, University of Birmingham, Whittall Street, Birmingham R Grundy, R G Gosden, M Hewitt, V Larcher, A Leiper, H A Spoudeas, D Walker, B4 6NH, UK R Grundy WHBWallace Department of Obstetrics and Gynaecology, Division of Reproductive Most children treated for cancer can now Biology, 687 Pine expect to be cured and to be fertile. However, Summary box 1—agents with proven Avenue West, in a significant minority, future fertility may be gonadotoxicity Montreal, QC Canada, compromised by their disease or its treatment.1 H3A1A1, Canada Alkylating agents R G Gosden Although the primary objective of treating can- + Cyclophosphamide cer is cure, this should be seen in the context of + Chlorambucil Queen’s Medical promoting and protecting the child’s overall + Melphalan Centre, University of wellbeing. Infertility may have significant + Busulfan Nottingham, psychological consequences in adulthood, and + Carmustine Nottingham NG7 2UH, strategies aimed at ameliorating this “cost of UK + Lomustine M Hewitt cure” provide new challenges to professionals + Mechlorethamine D Walker in many diVerent disciplines. + Procarbazine Cryopreservation of semen is well estab- + Cisplatin Department of lished for sexually mature boys,2 but there are + Nitrosoureas General Paediatric currently few options for peri- or prepubertal Vinca alkaloids Medicine, The Royal children. The use of donated gametes, sperm London Hospital, + Vinblastine Whitechapel, London or eggs, has recently become a realistic Antimetabolites http://adc.bmj.com/ E1 1BB, UK possibility in many centres and provides an + Cytosine arabinoside V Larcher option if treatment has provoked premature ovarian failure or azoospermia. Finally, gam- Department of etes, germ cells, and tissues can be collected reduction in fertility is seen. Most chemo- Haematology and and stored with the ultimate aim of enabling an Oncology, The therapy protocols use multiple agents whose Hospital for Sick individual to become a parent of a child that is eVects may be synergistic.6–14 Biochemical Children, Great genetically theirs. Possibilities for safeguarding detection of gonadal damage is rarely possible Ormond Street, future fertility vary from no medical interven- before puberty, so treatment induced gonadal on September 26, 2021 by guest. Protected copyright. London WC1N 3JH, tion to invasive procedures carrying more than damage in childhood may present with infertil- UK negligible risk in order to harvest gonadal ity or premature menopause in adulthood. A Leiper tissue. It is also important to recognise that although young cancer survivors are less likely Department of EVect of radiotherapy on gonadal to have children, this is not solely a result of Paediatric and function in boys and girls infertility. Many are unable to form long stand- Adolescent Sperm production is susceptible to damage at Endocrinology and ing peer relationships, others fear relapse of very low doses of irradiation (>1.2 Gy), but as Oncology, The their disease, and some fear the prospect of Leydig cell function is usually preserved up to Middlesex Hospital, leaving their child parentless.34 Mortimer Street, 12 Gy, it is possible for males who have Rapid developments in assisted reproduc- London W1N 8AA, UK sustained damage to the germinal epithelium H A Spoudeas tion techniques (ART) now raise the possibility to progress through puberty and retain po- of cryopreserving gonadal tissue to conserve tency.15 16 Department of the fertility of young cancer patients. These Abdominal, pelvic, and total body irradia- Haematology and advances raise major practical, scientific, and Oncology, Royal tion may all result in ovarian and uterine dam- ethical issues which are addressed in this and a 17 18 Hospital for Sick age. The human oocyte is sensitive to Children, 17 subsequent article. radiation, with an estimated LD50 of less than 4 Millerfield Place, Gy.19 Less than 2% of children receiving total Edinburgh E19 1LF, The problem: gonadal damage induced body irradiation subsequently became preg- UK 13 WHBWallace by chemotherapy in boys and girls nant or fathered a child, although there may Damage to the gonads by irradiation or be some protection of ovarian function in pre- Correspondence to: chemotherapy depends on the patients’ gender, pubertal girls.17 19 20 Uterine radiation increases Dr Grundy age at the time of treatment, radiation dose and the incidence of nulliparity, fetal loss, and small [email protected] fractionation schedule, and total dose and for dates infants,21 and reduces the success of Accepted 21 November 2000 nature of chemotherapy delivered.15 Overall a assisted reproduction.18 22 www.archdischild.com 356 Grundy, Gosden, Hewitt, Larcher, Leiper, Spoudeas, et al Summary box 2—radiotherapy induced Summary box 3—options for fertility Arch Dis Child: first published as 10.1136/adc.84.4.355 on 1 April 2001. Downloaded from damage to gonads preservation (boys) Boys Established + Azoospermia following low dose radio- + Sperm banking therapy (>1.2 Gy) Experimental + Leydig cell function preserved up to 12 + Rectal electrostimulation Gy + Testicular/epididymal aspiration of sper- Girls matocytes + Oocytes LD50 < 4Gy + Testicular biopsy cryopreservation and Total body irradiation—less than 2% of sur- future in vitro manipulation vivors become parents13 + Hormonal manipulation vention should only be carried out within ethi- Fertility preservation and assisted cally approved clinical trials. reproduction strategies for boys and girls Intracytoplasmic sperm injection into Advances in ART are particularly relevant to oocytes (ICSI) can reverse adult male infertil- prepubertal children who are currently ex- ity caused by oligospermia, early sperma- cluded from a number of strategies available to togenic arrest, or, in the case of patients with sexually mature patients. cancer, cryopreserved sperm of poor qual- ity.30 31 Immature spermatids extracted from STRATEGY FOR BOYS testicular tissue32–34 and more recently second- Spermatogenesis and steroidogenesis are func- ary spermatocytes35 have been used in ICSI, tions of the adult male testes, but spermatogen- but the number of successful pregnancies is esis starts prepubertally.23 It depends on the extremely low.36 37 Thus it appears possible to capacity of the totipotential stem cells to circumvent the maturation process from sper- undergo self renewal and provide progeny that matid to spermatozoa by injection of the mature into viable spermatocytes. Meiosis, haploid male nucleus into the oocyte. In with reduction to haploid chromosomal com- theory, haploid spermatids obtained from the plement, is a relatively early event and is com- testes of prepubescent boys may have repro- pleted by the time of maturation to spermatids; ductive potential, although this has not yet post-meiotic spermatocytes may occasionally been proven. be seen in children as young as 4 years.23 24 Although reduction to the haploid state has Peri- or postpubertal males who are Gillick occurred by the round spermatid phase it is not competent and sexually mature, may wish to clear that epigenetic, nuclear, and cytoplasmic undertake sperm banking before gonadotoxic modifications are complete by this stage. The 2 chemotherapy. (In English law the validity of a epigenetic phenomenon of imprinting is http://adc.bmj.com/ child’s consent to medical treatment depends thought to occur early in gametogenesis and on their capacity or competence to do so. plays an important role in embryogenesis.38 Under the Family Law Reform Act (1969) Disorders of imprinting are now recognised to children over 16 years can consent to medical cause human disease,39 40 and are implicated in treatment provided they are not incompetent. a number of malignancies including Wilms’ Children under the age of 16 may consent to tumour and embryonal rhabdomyo- treatment if they have suYcient understanding sarcoma.41–43 Careful clinical monitoring of and intelligence to enable them to understand children born following assisted conception is on September 26, 2021 by guest. Protected copyright. fully what is proposed. A child who can show essential in case unforseen problems arise.44 this ability is referred to as “Gillick competent” Totipotential germ cells isolated from the after the legal case in which judgement was testes of mice can repopulate sterilised mouse given.25) However, this is not “routine” practice testes, giving rise to functional sperm that can across UK Children’s Cancer Study Group fertilise oocytes and produce normal oV- centres, nor are there adequate adolescent spring.45 46 Similar results have now been “friendly” facilities. obtained with cryopreserved germ cells.47 The Spermarche is an early to mid-pubertal event techniques used are little diVerent from those and precedes the ability to produce an used for cryopreservation or ICSI, so that ejaculate.26 27 In peripubertal boys with sper- cryopreservation of biologically immortal and maturia, the possibility of obtaining a sperm unique human germline stem cells is a practical sample by electrostimulation should be consid- possibility, a development which has enormous ered,228 although facilities for this technique ethical and legal implications. Furthermore, are currently limited. Other options include xenogeneic transplantation
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