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

Abstract

Study question: What is the impact of cancer or hematological disorders on germ cells in pediatric male patients?

Summary answer: Spermatogonial 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 already: Fertility 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, duration: This 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, methods: In 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 chance: Prepubertal 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 caution: For 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 findings: Cancers, 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 number: N/A.

Keywords: fertility preservation; hematological disorders; male fertility; pediatric oncology; prepubertal boys; spermatogonia; testicular tissue cryopreservation.

Figure 1.

Spermatogonia per tubular cross-section in a patient population with cancer or hematological disorders and in simulated control datasets. S/T per patient per disease category and per hydroxyurea (HU) treatment against the reference values of spermatogonia per tubular cross-section in healthy prepubertal boys from the meta-analysis (Masliukaite et al., 2016). The vertical marking divides the graph to age groups of 0–4, 4–7, 7–11, and 11–14 years.

Figure 2.

Most advanced germ cell type by age group and disease group. Most advanced germ cell type in prepubertal boys at the time of testicular biopsy (prior to mainline therapy) per age group for each disease group (years) compared with age-matched controls. Numbers inside bars represent the number of patients. Control values in healthy prepubertal boys are from Nistal and Paniagua (1984) where spermatocytes and spermatids are presented in one category. SCO, Sertoli cell only; CNS, central nervous system.