Childhood cancer and hematological disorders negatively affect spermatogonial quantity at diagnosis: a retrospective study of a male fertility preservation cohort

Author:

Masliukaite Ieva12,Ntemou Elissavet3ORCID,Feijen Elizabeth A M4,van de Wetering Marianne4,Meissner Andreas1,Soufan Alexandre T1,Repping Sjoerd56,Kremer Leontien M C47,Jahnukainen Kirsi89,Goossens Ellen3ORCID,van Pelt Ans M M12ORCID

Affiliation:

1. Reproductive Biology Laboratory, Center for Reproductive Medicine, Amsterdam UMC, University of Amsterdam , Amsterdam, The Netherlands

2. Research Institute Amsterdam Reproduction & Development, Amsterdam UMC, University of Amsterdam , Amsterdam, The Netherlands

3. Biology of the Testis Lab, Department of Reproduction, Genetics and Regenerative Medicine, Vrije Universiteit Brussel (VUB) , Brussels, Belgium

4. Princess Maxima Center for Pediatric Oncology , Utrecht, The Netherlands

5. Amsterdam UMC, University of Amsterdam , Amsterdam, The Netherlands

6. The National Health Care Institute , Diemen, The Netherlands

7. Department of Pediatric Oncology, Emma Children's Hospital, Amsterdam UMC, Location AMC , Amsterdam, The Netherlands

8. NORDFERTIL Research Lab Stockholm, Department of Women’s and Children’s Health, Karolinska Institutet and University Hospital , Stockholm, Sweden

9. New Children’s Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital , Helsinki, Finland

Abstract

AbstractSTUDY QUESTIONWhat is the impact of cancer or hematological disorders on germ cells in pediatric male patients?SUMMARY ANSWERSpermatogonial quantity is reduced in testes of prepubertal boys diagnosed with cancer or severe hematological disorder compared to healthy controls and this reduction is disease and age dependent: patients with central nervous system cancer (CNS tumors) and hematological disorders, as well as boys <7 years are the most affected.WHAT IS KNOWN ALREADYFertility preservation in pediatric male patients is considered based on the gonadotoxicity of selected treatments. Although treatment effects on germ cells have been extensively investigated, limited data are available on the effect of the disease on the prepubertal male gonad. Of the few studies investigating the effects of cancer or hematologic disorders on testicular function and germ cell quantity in prepuberty, the results are inconsistent. However, recent studies suggested impairments before the initiation of known gonadotoxic therapy. Understanding which diseases and at what age affect the germ cell pool in pediatric patients before treatment is critical to optimize strategies and counseling for fertility preservation.STUDY DESIGN, SIZE, DURATIONThis multicenter retrospective cohort study included 101 boys aged <14 years with extra-cerebral cancer (solid tumors), CNS tumors, leukemia/lymphoma (blood cancer), or non-malignant hematological disorders, who were admitted for a fertility preservation programme between 2002 and 2018.PARTICIPANTS/MATERIALS, SETTING, METHODSIn addition to clinical data, we analyzed measurements of testicular volume and performed histological staining on testicular biopsies obtained before treatment, at cryopreservation, to evaluate number of spermatogonia per tubular cross-section, tubular fertility index, and the most advanced germ cell type prior to chemo-/radiotherapy. The controls were data simulations with summary statistics from original studies reporting healthy prepubertal boys’ testes characteristics.MAIN RESULTS AND THE ROLE OF CHANCEPrepubertal patients with childhood cancer or hematological disorders were more likely to have significantly reduced spermatogonial quantity compared to healthy controls (48.5% versus 31.0% prevalence, respectively). The prevalence of patients with reduced spermatogonial quantity was highest in the CNS tumor (56.7%) and the hematological disorder (55.6%) groups, including patients with hydroxyurea pre-treated sickle cell disease (58.3%) and patients not exposed to hydroxyurea (50%). Disease also adversely impacted spermatogonial distribution and differentiation. Irrespective of disease, we observed the highest spermatogonial quantity reduction in patients <7 years of age.LIMITATIONS, REASONS FOR CAUTIONFor ethical reasons, we could not collect spermatogonial quantity data in healthy prepubertal boys as controls and thus deployed statistical simulation on data from literature. Also, our results should be interpreted considering low patient numbers per (sub)group.WIDER IMPLICATIONS OF THE FINDINGSCancers, especially CNS tumors, and severe hematological disorders can affect spermatogonial quantity in prepubertal boys before treatment. Consequently, these patients may have a higher risk of depleted spermatogonia following therapies, resulting in persistent infertility. Therefore, patient counseling prior to disease treatment and timing of fertility preservation should not only be based on treatment regimes, but also on diagnoses and age.STUDY FUNDING/COMPETING INTEREST(S)This study was supported by Marie Curie Initial Training Network (ITN) (EU-FP7-PEOPLE-2013-ITN) funded by European Commision grant no. 603568; ZonMW Translational Adult stem cell research (TAS) grant no. 116003002. No competing interests.TRIAL REGISTRATION NUMBERN/A.

Funder

European Commision

Publisher

Oxford University Press (OUP)

Subject

Obstetrics and Gynecology,Rehabilitation,Reproductive Medicine

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