Fertility Preservation In Boys Research Articles

A 20-year overview of fertility preservation in boys: new insights gained through a comprehensive international survey.

Twenty years after the inception of the first fertility preservation programme for pre-pubertal boys, what are the current international practices with regard to cryopreservation of immature testicular tissue? Worldwide, testicular tissue has been cryopreserved from over 3000 boys under the age of 18 years for a variety of malignant and non-malignant indications; there is variability in practices related to eligibility, clinical assessment, storage, and funding. For male patients receiving gonadotoxic treatment prior to puberty, testicular tissue cryopreservation may provide a method of fertility preservation. While this technique remains experimental, an increasing number of centres worldwide are cryopreserving immature testicular tissue and are approaching clinical application of methods to use this stored tissue to restore fertility. As such, standards for quality assurance and clinical care in preserving immature testicular tissue should be established. A detailed survey was sent to 17 centres within the recently established ORCHID-NET consortium, which offer testicular tissue cryopreservation to patients under the age of 18 years. The study encompassed 60 questions and remained open from 1 July to 1 November 2022. Of the 17 invited centres, 16 completed the survey, with representation from Europe, Australia, and the USA. Collectively, these centres have cryopreserved testicular tissue from patients under the age of 18 years. Data are presented using descriptive analysis. Since the establishment of the first formal fertility preservation programme for pre-pubertal males in 2002, these 16 centres have cryopreserved tissue from 3118 patients under the age of 18 years, with both malignant (60.4%) and non-malignant (39.6%) diagnoses. All centres perform unilateral biopsies, while 6/16 sometimes perform bilateral biopsies. When cryopreserving tissue, 9/16 centres preserve fragments sized ≤5 mm3 with the remainder preserving fragments sized 6-20 mm3. Dimethylsulphoxide is commonly used as a cryoprotectant, with medium supplements varying across centres. There are variations in funding source, storage duration, and follow-up practice. Research, with consent, is conducted on stored tissue in 13/16 centres. While this is a multi-national study, it will not encompass every centre worldwide that is cryopreserving testicular tissue from males under 18 years of age. As such, it is likely that the actual number of patients is even higher than we report. Whilst the study is likely to reflect global practice overall, it will not provide a complete picture of practices in every centre. Given the research advances, it is reasonable to suggest that cryopreserved immature testicular tissue will in the future be used clinically to restore fertility. The growing number of patients undergoing this procedure necessitates collaboration between centres to better harmonize clinical and research protocols evaluating tissue function and clinical outcomes in these patients. K.D. is supported by a CRUK grant (C157/A25193). R.T.M. is supported by an UK Research and Innovation (UKRI) Future Leaders Fellowship (MR/S017151/1). The MRC Centre for Reproductive Health at the University of Edinburgh is supported by MRC (MR/N022556/1). C.L.M. is funded by Kika86 and ZonMW TAS 116003002. A.M.M.v.P. is supported by ZonMW TAS 116003002. E.G. was supported by the Research Program of the Research Foundation-Flanders (G.0109.18N), Kom op tegen Kanker, the Strategic Research Program (VUB_SRP89), and the Scientific Fund Willy Gepts. J.-B.S. is supported by the Swedish Childhood Cancer Foundation (TJ2020-0026). The work of NORDFERTIL is supported by the Swedish Childhood Cancer Foundation (PR2019-0123; PR2022-0115), the Swedish Research Council (2018-03094; 2021-02107), and the Birgitta and Carl-Axel Rydbeck's Research Grant for Paediatric Research (2020-00348; 2021-00073; 2022-00317; 2023-00353). C.E is supported by the Health Department of the Basque Government (Grants 2019111068 and 2022111067) and Inocente Inocente Foundation (FII22/001). M.P.R. is funded by a Medical Research Council Centre for Reproductive Health Grant No: MR/N022556/1. A.F. and N.R. received support from a French national research grant PHRC No. 2008/071/HP obtained by the French Institute of Cancer and the French Healthcare Organization. K.E.O. is funded by the University of Pittsburgh Medical Center and the US National Institutes of Health HD100197. V.B-L is supported by the French National Institute of Cancer (Grant Seq21-026). Y.J. is supported by the Royal Children's Hospital Foundation and a Medical Research Future Fund MRFAR000308. E.G., N.N., S.S., C.L.M., A.M.M.v.P., C.E., R.T.M., K.D., M.P.R. are members of COST Action CA20119 (ANDRONET) supported by COST (European Cooperation in Science and Technology). The Danish Child Cancer Foundation is also thanked for financial support (C.Y.A.). The authors declare no competing interests. N/A.

‘Fertility preservation in boys’

‘Fertility preservation in boys’

Fertility preservation in boys facing gonadotoxic cancer therapy.

Patient survival following childhood cancer has increased with contemporary radiation and chemotherapy techniques. However, gonadotoxicity associated with treatments means that infertility is a common consequence in survivors. Novel fertility preservation options are emerging, but knowledge about these options amongst urologists and other medical professionals is lacking. Pre-pubertal boys generally do not produce haploid germ cells. Thus, strategies for fertility preservation require cryopreservation of tissue containing spermatogonial stem cells (SSCs). Few centres worldwide routinely offer this option and fertility restoration (including testicular tissue engraftment, autotransplantation of SSCs and in vitro maturation of SSCs to spermatozoa) post-thaw is experimental. In pubertal boys, the main option for fertility preservation is masturbation and cryopreservation of the ejaculate. Assisted ejaculation using penile vibratory stimulation or electroejaculation and surgical sperm retrieval can be used in a sequential manner after failed masturbation. Physicians should inform boys and parents about the gonadotoxic effects of cancer treatment and offer fertility preservation. Preclinical experience has identified challenges in pre-pubertal fertility preservation, but available options are expected to be successful when today's pre-pubertal boys with cancer become adults. By contrast, fertility preservation in pubertal boys is clinically proven and should be offered to all patients undergoing cancer treatment.

Fertility preservation in boys: recent developments and new insights †.

BACKGROUNDInfertility is an important side effect of treatments used for cancer and other non-malignant conditions in males. This may be due to the loss of spermatogonial stem cells (SSCs) and/or altered functionality of testicular somatic cells (e.g. Sertoli cells, Leydig cells). Whereas sperm cryopreservation is the first-line procedure to preserve fertility in post-pubertal males, this option does not exist for prepubertal boys. For patients unable to produce sperm and at high risk of losing their fertility, testicular tissue freezing is now proposed as an alternative experimental option to safeguard their fertility.OBJECTIVE AND RATIONALEWith this review, we aim to provide an update on clinical practices and experimental methods, as well as to describe patient management inclusion strategies used to preserve and restore the fertility of prepubertal boys at high risk of fertility loss.SEARCH METHODSBased on the expertise of the participating centres and a literature search of the progress in clinical practices, patient management strategies and experimental methods used to preserve and restore the fertility of prepubertal boys at high risk of fertility loss were identified. In addition, a survey was conducted amongst European and North American centres/networks that have published papers on their testicular tissue banking activity.OUTCOMESSince the first publication on murine SSC transplantation in 1994, remarkable progress has been made towards clinical application: cryopreservation protocols for testicular tissue have been developed in animal models and are now offered to patients in clinics as a still experimental procedure. Transplantation methods have been adapted for human testis, and the efficiency and safety of the technique are being evaluated in mouse and primate models. However, important practical, medical and ethical issues must be resolved before fertility restoration can be applied in the clinic.Since the previous survey conducted in 2012, the implementation of testicular tissue cryopreservation as a means to preserve the fertility of prepubertal boys has increased. Data have been collected from 24 co-ordinating centres worldwide, which are actively offering testis tissue cryobanking to safeguard the future fertility of boys. More than 1033 young patients (age range 3 months to 18 years) have already undergone testicular tissue retrieval and storage for fertility preservation.LIMITATIONS, REASONS FOR CAUTIONThe review does not include the data of all reproductive centres worldwide. Other centres might be offering testicular tissue cryopreservation. Therefore, the numbers might be not representative for the entire field in reproductive medicine and biology worldwide. The key ethical issue regarding fertility preservation in prepubertal boys remains the experimental nature of the intervention.WIDER IMPLICATIONSThe revised procedures can be implemented by the multi-disciplinary teams offering and/or developing treatment strategies to preserve the fertility of prepubertal boys who have a high risk of fertility loss.STUDY FUNDING/COMPETING INTEREST(S)The work was funded by ESHRE. None of the authors has a conflict of interest.

Fertility preservation for boys and adolescents facing sterilizing medical therapy.

Improvements in childhood cancer survival have allowed boys and their families to increasingly focus on quality of life after therapy, particularly their future ability to father children. Treatments should maintain comprehensive cancer care goals and consider the long-term quality of life of these children. While semen cryopreservation is a well-established method of fertility preservation for post-pubertal children, the use of cryopreserved pre-treatment testicular tissue represents a promising, yet experimental method of fertility preservation for prepubertal males facing sterilizing therapy. Healthcare providers should counsel families about the fertility risks of therapy, discuss or refer patients for standard fertility preservation options, and consider experimental approaches to fertility preservation while being mindful of the ethical questions these treatments raise.

Electroejaculation as a method of fertility preservation in boys diagnosed with cancer: a single-center experience and review of the literature

To evaluate the feasibility of electroejaculation to perform semen cryopreservation in pubertal boys before gonadotoxic therapy and to review the literature on this topic. Retrospective cohort study and review of the literature. Academic children's hospital. Boys diagnosed with cancer to whom sperm cryopreservation was offered before the start of gonadotoxic therapy. We studied the outcome of electroejaculation, including patient characteristics, hormone levels, and pretreatment semen parameters. Semen cryopreservation. Pretreatment semen samples were obtained by masturbation in 106/114 boys with cancer, of which 78/106 were adequate for preservation. Electroejaculation was offered to 11 boys, of which three of 11 samples appeared adequate for preservation. Reviewing all reported electroejaculation cases in children with cancer in the literature, 13/29 (45%) cases were successful. Testosterone levels werehigher in patients with successful sperm yield obtained by electroejaculation (median, 8.3nmol/L [5.2-42.4] in successful harvests, vs. median 1.7nmol/L [0.01-17.9] in unsuccessful harvests). Semen cryopreservation should be offered to all pubertal boys diagnosed with cancer. If masturbation fails, electroejaculation can be considered as a useful option for semen cryopreservation and leads to adequate material for cryopreservation in about half of the cases.

Parental attitudes toward fertility preservation in boys with cancer: context of different risk levels of infertility and success rates of fertility restoration

To measure the parental attitudes toward fertility preservation in boys with cancer. Retrospective cohort study. Questionnaire survey via regular mail. A total of 465 families whose sons were already treated for cancer. The questionnaire was designed for two groups based on child's age at the time of cancer diagnosis: <12 and ≥12 years old. Descriptive statistics regarding a positive or negative attitude of parents toward fertility preservation options in the context of different risk levels of infertility and success rates of fertility restoration. The response rate was 78%. Sixty-four percent of parents of boys ≥12 years old would agree to store sperm obtained by masturbation and/or electroejaculation, and 54% of parents of boys <12 years old would agree to store a testicular biopsy. If the risk of infertility or the success rate of fertility restoration were ≤20%, more than one-fourth of parents would still opt for fertility preservation. All parents should be counseled about the risks of infertility due to cancer treatment, because many parents want to preserve their son's fertility even if the risk of becoming infertile or the chances on fertility restoration are low.

Parental attitudes toward fertility preservation in boys with cancer: context of different risk levels of infertility and success rates of fertility restoration

Parental attitudes toward fertility preservation in boys with cancer: context of different risk levels of infertility and success rates of fertility restoration

Fertility preservation for boys with cancer.

Childhood cancer is a curable disease due to the development of chemo- and radiation therapies, but long-term survivors suffer late side-effects including infertility. Cytotoxic agents and radiation impair spermatogenesis and cause oligospermia or azoospermia as well as genetic damage in sperm. To date, the only established option to preserve fertility is cryopreservation of sperm before treatment and artificial reproduction techniques, if men with cancer can ejaculate, but only a quarter of men have banked sperm. Lack of information is the most common reason for failing to bank sperm. However, prepubertal patients who have only spermatogonia and spermatocytes in their testes do not benefit from cryopreservation of their sperm and assisted reproductive techniques. Thus, the only available option is to harvest testicular tissues before treatment for cryopreservation, from which immature germ cells can somehow be maturated. Autotransplantation of germ cells into the testis holds promise for fertility restoration, but contamination by malignant cells may induce relapse. Fluorescence-activated cell sorting (FACS) with two surface markers could exclude contaminated leukemic cells from murine germ cells, and transplantation of sorted germ cells successfully restored fertility without transmission of leukemia. Human germ cells could be also isolated from human leukemia and lymphoma cell lines by FACS using surface markers. Before autotransplantation can be applied clinically, some issues, including the risk of contamination by malignant cells and in vitro propagation of spermatogonial stem cells, should be resolved.

Testicular stem cells for fertility preservation: Preclinical studies on male germ cell transplantation and testicular grafting

Spermatogonial stem cells open novel strategies for preservation of testicular tissue and fertility preservation in boys and men exposed to gonadotoxic therapies. This review provides an update on the physiology of spermatogonial stem cells in rodent and primate testes. Species-specific differences must be considered when new technologies on testicular stem cells are considered. Germ cell transplantation is presented as one novel and promising strategy. Whereas this technique has become an important research tool in rodents, a clinical application must still be regarded as experimental and many aspects of the procedure need to be optimized prior to a safe and efficient clinical application in men. Testicular grafting opens another exciting strategy for fertility preservation. Autologous and xenologous transfer of immature tissue revealed a high regenerative potential of immature testicular tissue. Grafting was applied in rodents and primates and resulted in the generation of sperm. Further research is needed before an application in humans can be considered safe and efficient. Despite the current limitations in regard to the generation of sperm from cryopreserved male germline cells and tissues, protocols for cryopreservation of testicular tissue are available and reveal a promising outcome. Since future improvements of germ cell transplantation and grafting approaches can be assumed, bioptic retrieval and cryopreservation of testicular tissue fragments should be performed in oncological patients at high risk of fertility loss since this is their only option to maintain their fertility potential.