Fertility Preservation in an Adolescent Boy: Inducing Puberty and Spermatogenesis Prior to Elective, Non-Urgent Bone Marrow Transplantation

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LETTER TO THE EDITOR Fertility preservation in an adolescent boy: inducing puberty and spermatogenesis prior to elective, non-urgent bone marrow transplantation

Bone Marrow Transplantation (2017) 52, 792–793; doi:10.1038/ 5450 mcg/L (NRo370). He was prepubertal, with 2 mL testes bmt.2017.6; published online 13 March 2017 bilaterally and with a height of 151.9 cm (50th centile) in a family with a mid-parental expectation on the 90th centile. His growth chart is shown in Figure 1. Bone marrow transplantation (BMT) has become an increasingly Discussion of fertility salvage options was undertaken, including common option for management of oncologic and other the likelihood that conditioning treatment with alkylating agents conditions in recent years. BMT involves the use of pre- prior to transplant would result in loss of all germ cells, with conditioning regimens that compromise fertility. Many condition- consequent sterility. The options were either to undertake ing regimens have devastating effects on the spermatogonial testicular biopsy of his prepubertal 2 mL testes, hoping to obtain stem cell pool, leading to lack of functional gametes and some spermatogonial cell lines (SCC) to be frozen for possible 2 consequent sterility. BMT is usually undertaken as an urgent or future maturation, or to induce puberty and hope to obtain semi-urgent procedure, either as a primary modality of cancer spermatogenesis, over a short time span, prior to transplant. care for high-risk leukaemias, after failed chemotherapy or relapse The former option is currently entirely experimental in of leukaemia, or less commonly in the setting of immune humans, although live progeny have resulted from similar 4,5 deficiency syndromes or bone marrow failures such as aplastic procedures in murine and simian (rhesus macaque) species. anaemia.1 Conversely, both semen storage and, if that failed, post-pubertal Occasionally for conditions such as thalassemia major, or testicular biopsy offer realistic hope of future fertility in the post- aplastic anaemia, it is possible to plan BMT within a longer time pubertal male. frame, wherein blood transfusions continue but marrow failure After discussion with the family, the boy and his parents chose predicates a need for further management. the option of pubertal induction. Initially he was followed clinically In adult men or in late peripubertal and postpubertal for 8 months, during which he remained prepubertal with 2 mL adolescent males, cryopreservation of ejaculated sperm or sperm testes bilaterally. Bone age was 13 years at a chronologic age of 13 obtained by testicular biopsy can provide assurance of an option years. BMT was scheduled to take place within 6–9 months. for future fertility, prior to gonadotoxic treatments. This strategy is Pubertal induction was commenced, using hCG 500 U twice per not available for prepubertal boys because spermatogenesis does week by subcutaneous injection and increasing to 1000 U twice not occur prior to puberty. Spermatogonial cell lines are present in weekly after 3 months. Pubertal progress was mildly accelerated the testes at birth. Foetal and postnatal gonocyte differentiation to and linear growth rate improved. When serum testosterone spermatogonia occurs progressively. Sertoli cells mature during reached an adult level of 11.9 nmol/L, FSH 150 IU × 3/week was childhood, germ cells proliferate, then seminiferous tubule added for induction of spermatogenesis and increased after outgrowth occurs in adolescence, with onset of spermatogenesis 3 months to 300 U thrice weekly. Over 9 months he grew 17.5 cm, sometime between ages 12 and 15 years.2 with a height achieved of 169.4 cm (50–75th centile). Adult Delayed puberty and hypogonadism are common in children virilization was present, with 20 mL testes bilaterally. Plasma with beta thalassemia major, due both to chronic disease and to testosterone was 17.6 nmol/L (NR 12–24), Inhibin B 135 ng/L (NR transfusion requirements. Despite chelation programmes, chronic 50–350). Semen collection was performed 9 months after iron overload remains a management challenge for many patients commencement of FSH, with 0.5–1.8 million/mL on three samples and their physicians. In addition to iron deposition in many other and cryopreservation of 11 straws. Four months after semen organs, the pituitary gland and, less commonly, the testes are collection he underwent BMT, preceded by busulphan targets for iron overload, with hypogonadism well recognized as a conditioning. complication of repeated blood transfusions.3 This report provides the first evidence of feasibility of inducing In addition, most chronic diseases are sufficiently debilitating, puberty and spermatogenesis adequate for future fertility, in a resulting in pubertal delay, which may require intervention in the young prepubertal adolescent male, prior to BMT. Fertility form of pubertal induction and hormonal support to complete preservation in this case is assured. Until recently, gonadotoxic normal linear growth and virilization in a boy or feminization in treatments that included high-dose alkylating agents in boys and a girl. peripubertal adolescent males were almost inevitably accompa- We describe the use of human chorionic gonadotrophin (hCG), nied by future infertility.6 Early reports of successful spermatogo- with later addition of follicle stimulating hormone (FSH) in a nial cell line salvage in mice, with later maturation, fertilization and 13-year-old boy with beta thalassemia major, one of two affected live progeny resulting have been followed by similar success in children in a family of three boys and two girls. Prior to bone monkeys.4,5 SCC salvage in prepubertal boys has been performed marrow transplant being planned within 12–15 months from the for more than 14 years and many centres are now considering or time of first endocrine consultation, the boy of age 12.2 years was offering this option. However, it remains experimental at this time, referred by his oncology team for discussion of possible fertility with no live births reported to date. preservation options. He had received regular blood transfusions A limited window of opportunity exists for inducing puberty in a every 3 weeks from age 2.5 years and had a history of suboptimal boy of 12–16 years, if time permits prior to gonadotoxin exposure. chelation for several years, with a current ferritin level of Pubertal induction with gonadotrophins is a safe, well-established Letter to the Editor 793 200 200

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70 70 24681012 14 16 18 20 Age (years) Figure 1. Growth chart of patient. A full color version of this ﬁgure is available at the Bone Marrow Transplantation journal online.

technique, used for pubertal induction in boys with congenital or 2Khoo Teck Puat-National University Children’s Medical Institute, childhood-onset hypothalamic hypogonadism. hCG is required for National University Health System, Singapore, Singapore and initiation and continuation of intra-testicular testosterone levels 3Department of Paediatrics, Yong Loo Lin School of Medicine, that are a prerequisite for supporting spermatogenesis. Successful National University of Singapore, Singapore, Singapore spermatogenesis is almost always achieved within 6–9 months of E-mail: [email protected] addition of FSH in these adolescent males.7 The only drawback of inducing puberty rapidly, as was undertaken for this boy, is rapid bone age advance with potential reduction in final height REFERENCES achieved. However, BMT with attendant peri-transplant illness 1 Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P et al. Hemato- and multiple immunosuppressive agent use over months is also poietic stem cell transplantation in Europe 2014: more than 40 000 transplants likely to have an adverse effect on pubertal progress and final annually. Bone Marrow Transplant 2016; 51:786–792. 2 Wyns C, Curaba M, Vanabelle B, Van Langendonckt A, Donnez J. Options for fertility height. This needs to be balanced against the success of fertility 16 – preservation. preservation in prepubertal boys. Hum Reprod Update 2010; :312 328. 3 Castaldi MA, Cobellis L. Thalassemia and infertility. Hum Fertil (Cam) 2016; 19: The option of pubertal induction with gonadotrophins 90–96. should be considered in future, for other adolescent males, prior 4 Wu X, Goodyear SM, Abramowitz LK, Bartolomei MS, Tobias JW, Avarbock MR et al. to gonadotoxic treatments, to ensure preservation of future Fertile offspring derived from mouse spermatogonial stem cells cryopreserved for fertility. more than 14 years. Hum Reprod 2012; 27: 1249–1259. 5 Hermann BP, Sukhwani M, Winkler F, Pascarella JN, Peters KA, Sheng Y et al. Spermatogonial stem cell transplantation into rhesus testes regenerates sperma- CONFLICT OF INTEREST togenesis producing functional sperm. Cell Stem Cell 2012; 11:715–726. The authors declare no conflict of interest. 6 Hudson MM. Reproductive outcomes for survivors of childhood cancer. Obstet Gynecol 2010; 116: 1171–1183. 1,2,3 1 7 Rohayem J, Hauffa BP, Zacharin M, Kliesch S, Zitzmann M. Testicular growth and CHo and M Zacharin spermatogenesis: new goals for pubertal hormone replacement in boys with 1 Department of Endocrinology, Murdoch Children’s Research hypogonadotropic hypogonadism? -a multicentre prospective study of hCG/rFSH Institute, Royal Children’s Hospital, Parkville, VIC, Australia; treatment outcomes during adolescence. Clin Endocrinol (Oxf) 2017; 86:75–87.