Search

Importance: Advances in the treatment of childhood cancer have significantly improved survival rates, with more than 80% of survivors reaching adulthood. However, gonadotoxic cancer treatments endanger future fertility, and prepubertal males have no option to preserve fertility by sperm cryopreservation. In addition, boys with cryptorchidism are at risk of compromised fertility in adulthood., Objective: To investigate current evidence for male fertility restoration strategies, explore barriers to clinical implementation, and outline potential steps to overcome these barriers, a scoping review was conducted. This knowledge synthesis is particularly relevant for prepubertal male cancer survivors and boys with cryptorchidism., Evidence Review: The review was conducted after the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews criteria and previously published guidelines and examined studies using human testis tissue of prepubertal boys or healthy male adults. A literature search in PubMed was conducted, and 72 relevant studies were identified, including in vivo and in vitro approaches., Findings: In vivo strategies, such as testis tissue engraftment and spermatogonial stem cell transplantation, hold promise for promoting cell survival and differentiation. Yet, complete spermatogenesis has not been achieved. In vitro approaches focus on the generation of male germ cells from direct germ cell maturation in various culture systems, alongside human induced pluripotent stem cells and embryonic stem cells. These approaches mark significant advancements in understanding and promoting spermatogenesis, but achieving fully functional spermatozoa in vitro remains a challenge. Barriers to clinical implementation include the risk of reintroducing malignant cells and introduction of epigenetic changes., Conclusion: Male fertility restoration is an area in rapid development. On the basis of the reviewed studies, the most promising and advanced strategy for restoring male fertility using cryopreserved testis tissue is direct testis tissue transplantation., Relevance: This review identifies persistent barriers to the clinical implementation of male fertility restoration. However, direct transplantation of frozen-thawed testis tissue remains a promising strategy that is on the verge of clinical application., Competing Interests: Declaration of Interests E.v.R. reports travel grant for the European Testis Workshop 2023 from the EU COST Action CA20119. C.F.S.J. has nothing to disclose. C.Y.A. reports consulting fees from Ferring Pharmaceuticals; honoraria from IBSA Pharma and Ferring Pharmaceuticals; and stock options from ARTSMedia Denmark, outside the submitted work. J.O.R.S. reports a grant from the Independent Research Fund Denmark (grant number 2096-00027B) for the submitted work. J.F. has nothing to disclose. J.T. reports royalties from Springer-Verlag – Textbook and institutional support for attending European Society for Paediatric Urology congress and European Paediatric Surgeons’ Association congress, outside the submitted work. D.A.O. has nothing to disclose. M.F. has nothing to disclose. E.R.H. reports funding from Greater Copenhagen Health Science Partners and Danish National Science Foundation (DNRF115) for the submitted work; funding from Novo Nordisk Foundation (NNFOC0074308 and NNF21OC0066487); honoraria for lectures from Ferring Pharmaceuticals (October 29–30, 2022, Copenhagen, Denmark), Takeda Science Foundation (Osaka, Japan), and Merck (October 25, 2022, Rungstedlund, Copenhagen, Denmark), and for Doctor of Philosophy examination from Crick Institute; travel support for the 2024 Gordon Research Conference on Meiosis (invited speaker); and waiver for conference fees by the Gordon Research Conference; support for conference attendance (room and board) for the Memorial Sloan Kettering Cancer Center–Crick–University of Copenhagen Conference (invited speaker; May 9–11, 2024) from the organizer; travel and hotel fees for the Wellcome Trust interview (January 23, 2024) at the Wellcome Trust, Novo Nordisk Foundation; support for travel and conference attendance for the Protein Signaling Conference (invited speaker; November 27, 2023, to December 1, 2023) from the organizer; waiver for conference fees and travel support for the European Society of Human Reproduction and Embryology (ESHRE) Campus Course, Florence, Italy (invited speaker; November 9–11, 2023) from ESHRE; travel and subsistence fees for the Danish National Research Foundation – Early Career Research Conference (invited speaker; November 11, 2023) from the organizers; conference and subsistence fees for the Aging Research and Drug Discovery Conference, Copenhagen (invited speaker; August 28, 2023, to September 1, 2023), from the organizers; conference, subsistence, room, and travel fees for the Gordon Conference on Aging 2023 (invited speaker; July 3–9, 2023), from the organizers; conference, room, and subsistence fees for the ESHRE Conference (invited speaker; June 26–28, 2023), from the organizers; travel, room, and subsistence fees for the Takeda Conference (invited speaker; January 24–27, 2023), from the Takeda Foundation; travel, room, and subsistence fees for the Origin of Aneuploidy (invited speaker; November 12–13, 2022), from the Origins of Aneuploidy Research Consortium; and travel, room, and subsistence fees for the ReproYoung Conference (invited Board Member of ReproUnion; May 28–29, 2022, Saltsjøbadet, Ystad, Sweden), from ReproUnion and is Chair of the Committee for Disputas, University of Lund, Sweden; Scientific Advisory Board of Institut Curie; Member of the Independent Research Fund Denmark–Committee for Health and Disease, National Granting Committee (January 1, 2021, to December 31, 2023); Steering Group Member of the Danish Korean Rights Group; and Member of the National Committee for Infrastructure, Ministry of Higher Education and Research, Denmark, outside the submitted work. L.S.M. has nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

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., (© 2021. Springer Nature Limited.)

Objective: To evaluate the use of cryopreserved ovarian tissue in the Danish fertility preservation cohort., Design: Retrospective cohort study., Setting: University hospitals and fertility clinics., Patient(s): Ovarian tissue cryopreservation (OTC) was performed for 1,186 Danish girls and women from 1999-2020, of whom 117 subsequently underwent ovarian tissue transplantation (OTT). Subgroup 1 included 759 patients with a follow-up period of >5 years. Out of these, OTT rates were further analyzed for those patients who were alive and aged >24 years in July 2020 (subgroup 2; n = 554)., Intervention(s): OTC and OTT., Main Outcome Measure(s): OTT, death, donation of tissue., Result(s): In subgroup 1, 14% of the patients had undergone OTT, 18% had died, 9% had donated their tissue for research, and 59% still had their tissue stored. In subgroup 2, 19% had undergone OTT and for most diagnoses the OTT rates ranged from 15% to 22% with benign hematologic diseases having the highest OTT rate (35%). On the basis of the entire cohort, stratified age analysis indicated that women aged ≥30 years at OTC were more likely to return for OTT than women aged 18-29 years at OTC; mean storage times were 3.7 and 3.6 years, respectively. Only 4% of the girls aged <18 years at OTC had undergone OTT., Conclusion(s): The OTT rates depended on the diagnosis, age at OTC, and follow-up time. Specific criteria are needed for reporting and comparing OTT rates. Six out of 10 patients still had their cryopreserved tissue stored and longer follow-up is needed, especially for younger girls., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Study Question: What are the results of transplanting cryopreserved ovarian tissue?, Summary Answer: The transplanted ovarian tissue can last up to 10 years, with no relapses following the 53 transplantations, and the chance of a successful pregnancy is currently around one in three for those with a pregnancy-wish., What Is Known Already: Cryopreservation of ovarian tissue is now gaining ground as a valid method for fertility preservation. More than 36 children worldwide have now been born following this procedure., Study Design, Size, Duration: This is a retrospective cohort study of 41 women who had thawed ovarian tissue transplanted 53 times over a period of 10 years, including 1 patient who was lost to follow-up., Participants/materials, Setting, Methods: The 41 Danish women, who had in total 53 transplantations, were followed for ovarian function and fertility outcome. Safety was assessed by monitoring relapse in cancer survivors., Main Results, and the Role of Chance: Among 32 women with a pregnancy-wish, 10 (31%) had a child/children (14 children in total); this included 1 woman with a third trimester on-going pregnancy. In addition, two legal abortions and one second trimester miscarriage occurred. A total of 24 clinical pregnancies were established in the 32 women with a pregnancy-wish. The tissue remained functional for close to 10 years in some cases and lasted only a short period in others. Three relapses occurred but were unlikely to be due to the transplanted tissue., Limitations, Reasons for Caution: Self-report through questionnaires with only in-one hospital formalised follow-up of transplanted patients could result in unreported miscarriages. The longevity of the tissue may vary by few months compared with those reported because some patients simply could not remember the date when the tissue became non-functional., Wider Implications of the Findings: Cryopreservation of ovarian tissue is likely to become integrated into the treatment of young women, with cancer, who run a risk of losing their fertility. The full functional lifespan of grafts is still being evaluated, because many of the transplanted women have continued to maintain ovarian activity. Some of our first cases have had tissue functioning for ∼ 10 years., (© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Nonspermatozoal cells (NSC) in semen, including immature germ cells, leukocytes (WBC) and epithelial cells, are normally found in a concentration less than 15% of the sperm concentration. Cytological staining methods and immunoenzymatic assays for characterization of seminal WBC and methods for detection of various enzymes from WBC are evaluated. Criteria for abnormally high levels of WBC in semen, caused by exogenic factors (e.g., infection) and possibly by endogenic factors (e.g., abnormal sperm), are discussed. Leukocytospermia is associated with reduced in vitro fertilization rate, and experimentally-measured sperm functions (e.g., motility) are inhibited by high concentrations of certain WBC products (e.g., reactive oxygen species and interferon-gamma). At the present stage, the following procedures could be used to evaluate WBC in ejaculates from infertile patients: (1) count the number of NSC using a hemocytometer. (2) Determine the number of WBC in percentage of NSC in smears using the Papanicolaou staining technique, or an immuno-enzymatic assay using monoclonal antibodies to the different kinds of WBC. (3) If, abnormally high levels of WBC (according to the WHO criteria or based on a percentile determined from examination of normal, fertile men) is detected, a second ejaculate should be examined 3 months later. (4) Persistent leukocytospermia should indicate physical and microbiological examinations, after which antibiotic treatment may be indicated.

In semen samples from 94 men from infertile couples and 42 control patients proven to be fertile the occurrence of different kinds of nonspermatozoal cells (NSC) was examined. The findings were evaluated in relation to other seminal parameters and to the fertility status of the couple. The ratios of NSC to sperm and primary spermatocytes to spermatids revealed increasing values with decreasing sperm counts. Especially in a group where the semen samples contained > or = 6 x 10(6) motile sperm per mL and no infertility factor was detectable in the woman, the concentration of leukocytes was high, with three of eight patients having > or = 10(6) leukocytes per mL. A high proportion of abnormal sperm seemed to occur more frequently where the cause of infertility could be found in the man. A high number of leukocytes was neither significantly associated to an increased proportion of abnormal sperm nor to sperm motility evaluated by recording the percentage of motile sperm and the 1-h migration distance in sodium hyaluronate medium. No correlation between concentration of lymphocytes and presence of antisperm antibodies in seminal plasma was detectable.

Study Question: Is there an association between the need for medical puberty induction and the diagnosis or treatment received in girls who have undergone cryopreservation of ovarian tissue for fertility preservation?Summary Answer: There was a clear association between the intensity of treatment received and requirement for medical puberty induction but no association with the diagnosis.What Is Known Already: Although it cannot be predicted which girls will become infertile or develop premature ovarian insufficiency (POI) following intensive chemotherapy or irradiation, patients who are at high risk of POI should be offered ovarian tissue cryopreservation (OTC). This includes girls who are planned to receive either high doses of alkylating agents, conditioning regimen before stem cell transplantation (SCT), total body irradiation (TBI) or high radiation doses to the craniospinal, abdominal or pelvic area.Study Design, Size, Duration: This is a retrospective cohort study. In total, 176 Danish girls under 18 years of age have had OTC performed over a period of 15 years. An overview of the girls' diagnoses and mean age at OTC as well as the number of deceased is presented. Of the 176 girls, 38 had died and 46 girls were still younger than 12 years so their pubertal development cannot be evaluated yet. For the 60 girls who had OTC performed after 12 years of age, the incidence of POI was evaluated and in the group of 32 girls who were younger than 12 years at OTC, the association between the diagnosis and received treatment and the requirement for medical puberty induction was examined.Participants/materials, Setting, Methods: The need for medical puberty induction was assessed in 32 girls who were prepubertal at the time of OTC.Main Results and the Role Of Chance: Indications for OTC were allogeneic SCT for leukaemia, myelodysplastic syndrome or benign haematological disorders, autologous SCT for lymphoma or sarcoma, and irradiation to the pelvis or to the spinal axis. The mean age at OTC of the 176 girls were 11.3 years. The two most prevalent diagnoses of the 176 girls were malignant tumours and malignant haematological diseases. Among the 32 prepubertal girls, 12 received high dose chemotherapy and either TBI prior to SCT or irradiation to the pelvis, abdomen or the spinal axis, 13 received high dose alkylating agents but no irradiation prior to SCT, six received alkylating agents as part of conventional chemotherapy and one patient had a genetic metabolic disorder and did not receive gonadotoxic treatment. Among these 32 girls, 23 did not undergo puberty spontaneously and thus received medical puberty induction. Among the nine girls, who went through spontaneous puberty, four had received high dose alkylating agents and five had received conventional chemotherapy.Limitations Reasons For Caution: All information was retrieved retrospectively from patient records, and thus some information was not available.Wider Implications Of the Findings: OTC should be recommended to all young girls, who present a high risk of developing ovarian insufficiency and/or infertility following high dose chemotherapy and/or irradiation.Study Funding/competing Interests: The Childhood Cancer Foundation (2012-2016) and the EU interregional project ReproHigh are thanked for having funded this study. They had no role in the study design, collection and analysis of the data or writing of the report. The authors have no conflict of interest to disclose. [ABSTRACT FROM AUTHOR]