Imatinib damages testes via c-KIT/PDGFR inhibition; neonatal exposure carries high irreversibility risk, adult exposure is more forgiving
Journal: Frontiers in Endocrinology | Published: 2026-05-14 | Type: Scoping Review | PMID: 42222081 Authors: Ji Xia (Inner Mongolia Baogang Hospital), Ahmad Mohd Faizal, Mokhtar Mohd Helmy, He XiaoYing, Abdul Karim Abdul Kadir (Universiti Kebangsaan Malaysia) Funding/COI: Not listed. Authors declared no commercial or financial conflicts.
Imatinib (Gleevec), the tyrosine kinase inhibitor that transformed CML and GIST treatment, suppresses c-KIT and PDGFR signaling pathways that are also essential for normal spermatogenesis. This scoping review of 20 preclinical and clinical studies finds dose-dependent reductions in testosterone and sperm density, with the key variable being age at exposure: adult men on standard 400 mg/day dosing sometimes maintain functional fertility and have fathered children during treatment, while neonatal and prepubertal exposure in animal models consistently produces partial or irreversible testicular damage. The gap between animal and human findings is large enough that preclinical data should not be extrapolated directly to clinical risk counseling.
This is a scoping review, which by design maps available evidence without formally appraising study quality or conducting risk-of-bias assessment — the authors are explicit about this limitation. The 20 included studies span animal models (often using intraperitoneal injection or oral gavage at doses higher than clinical equivalents), in vitro systems, and human cohorts. That's a heterogeneous pool that resists synthesis. The authors acknowledge the key translational problem forthrightly: animal studies target neonatal/prepubertal animals, most clinical data come from adults, and the outcome measures don't match (histology vs. semen analysis and hormonal profiling). No meta-analysis was attempted, and none would be appropriate given the data.
Clinical human studies are consistently characterized as small sample sizes, retrospective design, and heterogeneous treatment durations — the authors flag these limitations repeatedly. The honest conclusion from this review is that the existing clinical evidence base is thin.
This review earns its place in the literature by being honest about what it can and cannot conclude. It maps a real mechanistic concern — imatinib does suppress pathways critical to spermatogenesis — while correctly refusing to overstate clinical risk from animal data. The actionable takeaway is developmental-stage-specific: adult CML patients on standard dosing face uncertain but possibly modest fertility risk, while prepubertal or neonatal exposure is a different and more serious proposition. The evidence base for the adult clinical risk is genuinely thin, and this paper does not pretend otherwise. It is a serviceable map of a poorly-charted field, not a definitive assessment of harm.