STUDY QUESTION 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? SUMMARY ANSWER Based on a review of the clinical literature and research evidence for sperm freezing and testicular tissue cryopreservation, and after consideration of the relevant ethical and legal challenges, an algorithm for the cryopreservation of sperm and testicular tissue is proposed for prepubertal boys and adolescent males at high risk of fertility loss. WHAT IS KNOWN ALREADY A known late effect of the chemotherapy agents and radiation exposure regimes used to treat childhood cancers and other non-malignant conditions in males is the damage and/or loss of the proliferating spermatogonial stem cells in the testis. Cryopreservation of spermatozoa is the first line treatment for fertility preservation in adolescent males. Where sperm retrieval is impossible, such as in prepubertal boys, or it is unfeasible in adolescents prior to the onset of ablative therapies, alternative experimental treatments such as testicular tissue cryopreservation and the harvesting and banking of isolated spermatogonial stem cells can now be proposed as viable means of preserving fertility. STUDY DESIGN, SIZE, DURATION Advances in clinical treatments, patient management strategies and the research methods used to preserve sperm and testicular tissue for prepubertal boys and adolescents were reviewed. A snapshot of the up-take of testis cryopreservation as a means to preserve the fertility of young males prior to December 2012 was provided using a questionnaire. PARTICIPANTS/MATERIALS, SETTING, METHODS A comprehensive literature review was conducted. In addition, survey results of testis freezing practices in young patients were collated from 24 European centres and Israeli University Hospitals. MAIN RESULTS AND THE ROLE OF CHANCE There is increasing evidence of the use of testicular tissue cryopreservation as a means to preserve the fertility of pre- and peri-pubertal boys of up to 16 year-old. The survey results indicate that of the 14 respondents, half of the centres were actively offering testis tissue cryobanking as a means of safeguarding the future fertility of boys and adolescents as more than 260 young patients (age range less than 1 year old to 16 years of age), had already undergone testicular tissue retrieval and storage for fertility preservation. The remaining centres were considering the implementation of a tissue-based fertility preservation programme for boys undergoing oncological treatments. LIMITATIONS, REASONS FOR CAUTION The data collected were limited by the scope of the questionnaire, the geographical range of the survey area, and the small number of respondents. WIDER IMPLICATIONS OF THE FINDINGS The clinical and research questions identified and the ethical and legal issues raised are highly relevant to the multi-disciplinary teams developing treatment strategies to preserve the fertility of prepubertal and adolescent boys who have a high risk of fertility loss due to ablative interventions, trauma or genetic pre-disposition. STUDY FUNDING/COMPETING INTEREST(S) The work was funded by the European Society of Human Reproduction and Embryology (ESHRE).

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A European perspective on testicular tissue cryopreservation for fertility preservation in prepubertal and adolescent boys

Background We undertook a systematic review and meta-analysis of perinatal variables in relation to testicular cancer risk, with a specific focus upon characteristics of the mother.

Methods EMBASE, PubMed, Scopus and Web of Science databases were searched using sensitive search strategies. Meta-analysis was undertaken using STATA 10.

Results A total of 5865 references were retrieved, of which 67 met the inclusion criteria and contributed data to at least one perinatal analysis. Random effects meta-analysis found maternal bleeding during pregnancy [odds ratio (OR) 1.33, 95% confidence interval (CI) 1.02–1.73], birth order (primiparous vs not, 1.08, 95% CI 1.01–1.16; second vs first, OR 0.94, 95% CI 0.88–0.99; third vs first, OR 0.91, 95% CI 0.83–1.01; fourth vs first, OR 0.80, 95% CI 0.69–0.94) and sibship size (2 vs 1, OR 0.93, 95% CI 0.75–1.15; 3 vs 1, OR 0.89, 95% CI 0.74–1.07; 4 vs 1, OR 0.75, 95% CI 0.62–0.90) to be associated with testicular cancer risk. Meta-analyses that produced summary estimates which indicated no association included maternal age, maternal nausea, maternal hypertension, pre-eclampsia, breech delivery and caesarean section. Meta-regression provided evidence that continent of study is important in the relationship between caesarean section and testicular cancer (P = 0.035), and a meta-analysis restricted to the three studies from the USA was suggestive of association (OR 1.67, 95% CI 1.07–2.56).

Conclusions This systematic review and meta-analysis has found evidence for associations of maternal bleeding, birth order, sibship size and possibly caesarean section with risk of testicular cancer.

A systematic review and meta-analysis of perinatal variables in relation to the risk of testicular cancer-experiences of the son.

Background Germ cell depletion caused by chemical or physical toxicity, disease or genetic predisposition can occur at any age. Although semen cryopreservation is the first reflex for preserving male fertility, this cannot help out prepubertal boys. Yet, these boys do have spermatogonial stem cells (SSCs) that able to produce sperm at the start of puberty, which allows them to safeguard their fertility through testicular tissue (TT) cryopreservation. SSC transplantation (SSCT), TT grafting and recent advances in in vitro spermatogenesis have opened new possibilities to restore fertility in humans. However, these techniques are still at a research stage and their efficiency depends on the amount of SSCs available for fertility restoration. Therefore, maintaining the number of SSCs is a critical step in human fertility preservation. Standardizing a successful cryopreservation method for TT and testicular cell suspensions (TCSs) is most important before any clinical application of fertility restoration could be successful. Objective and rationale This review gives an overview of existing cryopreservation protocols used in different animal models and humans. Cell recovery, cell viability, tissue integrity and functional assays are taken into account. Additionally, biosafety and current perspectives in male fertility preservation are discussed. Search methods An extensive PubMED and MEDline database search was conducted. Relevant studies linked to the topic were identified by the search terms: cryopreservation, male fertility preservation, (immature)testicular tissue, testicular cell suspension, spermatogonial stem cell, gonadotoxicity, radiotherapy and chemotherapy. Outcomes The feasibility of fertility restoration techniques using frozen-thawed TT and TCS has been proven in animal models. Efficient protocols for cryopreserving human TT exist and are currently applied in the clinic. For TCSs, the highest post-thaw viability reported after vitrification is 55.6 ± 23.8%. Yet, functional proof of fertility restoration in the human is lacking. In addition, few to no data are available on the safety aspects inherent to offspring generation with gametes derived from frozen-thawed TT or TCSs. Moreover, clarification is needed on whether it is better to cryopreserve TT or TCS. Wider implications Fertility restoration techniques are very promising and expected to be implemented in the clinic in the near future. However, inter-center variability needs to be overcome and the gametes produced for reproduction purposes need to be subjected to safety studies. With the perspective of a future clinical application, there is a dire need to optimize and standardize cryopreservation and safety testing before using frozen-thawed TT of TCSs for fertility restoration.

Cryopreservation of testicular tissue or testicular cell suspensions: a pivotal step in fertility preservation

Background Significant variability exists for the relative risk (RR) of testicular malignancy in isolated cryptorchidism. Objective To perform a meta-analysis to clarify the true magnitude of this risk, allowing clinicians to better counsel patients and their families. Setting Secondary research conducted by undergraduate researchers, clinical academics and a clinical statistician. Design, data sources, and methods A search of the English literature was performed for studies relating to testicular cancer and cryptorchidism, published between 1 January 1980 and 31 December 2010, using Embase and Medline databases. 735 papers were identified and analysed by four authors independently in accordance with our inclusion and exclusion criteria. Studies reporting an association between cryptorchidism and subsequent development of testicular malignancy were included. Genetic syndromes or other conditions which predisposed to the development of cryptorchidism were excluded. Pooled estimates and 95% CIs for the RRs were calculated. Results Nine case–control studies and three cohort studies were selected. The case–control studies included 2281 cases and 4811 controls. Cohort studies included 2 177 941 boys, with a total of 345 boys developing testicular cancer (total length of follow-up was 58 270 679 person-years). The pooled RR was 2.90 (95% CI 2.21 to 3.82) with significant heterogeneity (p 2 =89%). Conclusion Boys with isolated cryptorchidism are three times more likely to develop testicular cancer. The limitations of this study must be acknowledged, in particular, possible publication bias and the lack of high-quality evidence focusing on the risk of malignancy in boys with isolated cryptorchidism.

https://adc.bmj.com/content/archdischild/98/1/20.full.pdf

A meta-analysis of the risk of boys with isolated cryptorchidism developing testicular cancer in later life

/pdf/synthetic-conception-artificial-insemination-and-the-1ywj5hdaru.pdf

Synthetic conception: artificial insemination and the transformation of reproduction and family in nineteenth and twentieth century America

Sperm cryopreservation in adolescents and young adults with cancer: results of the French national sperm banking network (CECOS).

Testicular cancer (TC) risk factors remain largely unknown, except for personal history of cryptorchidism and familial history of TC. We conducted a hospital-based case-control study on familial, environmental and occupational conditions in which we compared 229 cases and 800 controls. TC was correlated with cryptorchidism (OR = 3.02; CI: 1.90-4.79), a history of cryptorchidism in relatives (OR = 2.85; CI: 1.70-4.79), and TC (OR = 9.58; CI: 4.01-22.88], prostate cancer (OR = 1.80; CI: 1.08-3.02) and breast cancer (OR = 1.77; CI: 1.20-2.60) in relatives. Living in a rural area or having regular gardening activity (growing fruit or vegetables) was associated with an increased risk of TC (OR = 1.63; CI: 1.16-2.29; OR = 1.84; CI: 1.23-2.75). Regarding occupation, we found a relationship with employment in metal trimming (OR = 1.96; CI: 1.00-3.86), chemical manufacture (OR = 1.88; CI: 1.14-3.10), industrial production of glue (OR = 2.21; CI: 1.15-4.25), and welding (OR = 2.84; CI: 1.51-5.35). In a multivariate model, only a history of cryptorchidism in the men, cryptorchidism in relatives, TC, and breast cancer remained significant. Our findings contribute further evidence to a pattern of TC risk factors, which include the significant weight of personal reproductive history and also of testicular and breast cancer in relatives. By including in a multivariate model variables linked to environmental and occupational exposure and related to familial cancer history, neither living in a rural area nor any occupational exposure appeared to be a potential environmental TC risk factor.

Dominique Le Lannou

Papers

Sperm cryopreservation in adolescents and young adults with cancer: results of the French national sperm banking network (CECOS).

Environmental, occupational and familial risks for testicular cancer: a hospital-based case-control study.

High incidence of chromosomal abnormalities in oocyte donors.

Semen Donor Insemination