What is the prevalence of infertility in male survivors of childhood leukemia?

Prevalence of Infertility After Childhood Leukemia Treatment in Males

Male survivors of childhood leukemia face a 25-34% prevalence of suspected infertility when formally tested, though the majority retain normal fertility, with outcomes heavily dependent on specific treatment exposures—particularly alkylating agent doses and radiation fields.

Treatment-Specific Infertility Risks

High-Risk Treatments

• Cyclophosphamide doses >7.5 g/m² carry high risk of permanent infertility, with cumulative doses >9.5 g/m² associated with permanent azoospermia 1
• Testicular radiation ≥2 Gy can cause permanent azoospermia, while doses ≥20 Gy result in both germ cell and Leydig cell dysfunction 1
• Total body irradiation (TBI) used in hematopoietic stem cell transplantation results in permanent infertility in most males 1, 2
• Procarbazine-based regimens (MOPP) cause azoospermia in >90% of men, often permanent 1

Moderate-Risk Treatments

• High-dose cranial radiotherapy (24 Gy) administered before age 10 reduces fertility to 9% of controls through hypothalamic-pituitary dysfunction 3
• Busulfan >600 mg/m² or ifosfamide >60 mg/m² are considered high-risk alkylating exposures 1

Lower-Risk Treatments

• Standard ALL chemotherapy without high-dose alkylators or radiation shows fertility comparable to controls 4
• ABVD regimen is less gonadotoxic, with most patients regaining normal fertility after treatment 1

Documented Prevalence Data

Formal Testing Studies

• Among 104 male leukemia survivors who underwent fertility testing, 26% (95% CI: 18-34%) had suspected infertility 5
• In a Berlin cohort of 59 leukemia survivors tested, 25% (95% CI: 14-36%) had suspected infertility based on FSH >10 IU/L, inhibin B <80 pg/mL, or azoospermia 5
• A separate study of 230 male ALL survivors showed no overall fertility difference from controls (relative fertility 0.95% CI: 0.63-1.43), though specific high-risk subgroups were affected 3

Proven Fertility Outcomes

• Among male ALL survivors attempting conception, 69% succeeded compared to 61% of controls (not statistically different, P=0.50) 4
• However, partners of male survivors experienced significantly higher miscarriage rates (28.1% vs 5.9%, P=0.021) 4

Recovery Timeline and Prognosis

Azoospermia Recovery Patterns

• Azoospermia rates are highest within the first 12 months post-treatment, with nadir at 2-6 years 1, 6
• Most recovery of spermatogenesis occurs 2-3 years after treatment completion if it occurs at all 1, 6
• Little chance of recovery exists after 10 years of persistent azoospermia following radiotherapy or chemotherapy 1
• Semen analysis within the first 12 months post-treatment has limited clinical value 1, 6

Treatment-Specific Recovery

• Cisplatin-based regimens show 50% recovery at 2 years and 80% at 5 years 1, 6
• Procarbazine-based regimens rarely show recovery, resulting in permanent infertility 1, 6

Critical Clinical Pitfalls

Counseling Failures

• Only 26-83% of patients receive fertility counseling before treatment, despite NCCN and ASCO mandates 1, 2
• Among adolescent boys at risk, only 53.4% attempted sperm banking, with 43.8% successfully banking 1, 2
• Regular menstruation or normal testosterone levels do not guarantee fertility—germ cell dysfunction is more common than Leydig cell dysfunction 1, 2

Timing Errors

• Fertility preservation must occur before treatment initiation, as even diagnostic delays can compromise options 1, 2
• Contraception should continue even after prolonged azoospermia, as late recovery is possible 1
• Men should avoid conception for 12 months after completing gonadotoxic therapy due to mutagenic effects 1

Assessment Mistakes

• Performing semen analysis too early (<2 years post-treatment) provides misleading information 1, 6
• Assuming young age at treatment is protective—prepubertal boys receiving high-dose alkylators or TBI face similar or higher risks 2, 7

Fertility Preservation Recommendations

Standard Approach

• Sperm cryopreservation is the only established fertility preservation method for post-pubertal males and should be offered to all patients before treatment 1, 2
• Collection can occur every 24 hours as needed to obtain adequate samples 2
• For prepubertal boys, testicular tissue cryopreservation remains experimental but should be considered for those at highest risk 1, 7

Long-Term Surveillance

• Assessment of puberty, Tanner staging, and gonadal function should occur annually until sexual maturity 2
• Baseline LH, FSH, and testosterone should be measured at age 13 in prepubertal survivors 2
• Formal fertility testing (semen analysis) is most valuable 2-3 years post-treatment 1, 6