Short-course letrozole restores fertility in aged azoospermic dogs

Introduction Age-related azoospermia is a clinically important cause of male infertility in dogs, yet effective pharmacological treatments for aged males remain limited. Whether transient aromatase inhibition can restore fertility in aged azoospermic dogs without prolonged exposure is unclear. Methods This study evaluated whether a 1-week course of letrozole, an aromatase inhibitor, could restore spermatogenesis and fertility in aged azoospermic male dogs. Untreated aged azoospermic and young fertile dogs served as comparison groups, and a separate cohort of five aged dogs received 3 months of letrozole for safety assessment. Serum testosterone, semen parameters, testicular histology, fertilization-related transcripts, spermatogonia, seminal plasma metabolites, and serum biochemical markers of liver, kidney, and bone metabolism were assessed before and after treatment over a 6-month follow-up. Results Serum testosterone increased within 1 week and peaked at approximately 2 weeks. Spermatozoa reappeared in ejaculates approximately 3 months after treatment and persisted for more than 6 months; treated males subsequently achieved pregnancies with healthy offspring, although litter size remained smaller than that of young fertile dogs. Compared with 3-month administration, 1-week treatment was not associated with detectable changes in serum alkaline phosphatase (ALP). Discussion These findings indicate that a 1-week letrozole course can restore spermatogenesis and fertility in aged azoospermic dogs, supporting its further evaluation as a low-exposure therapeutic strategy; larger, breed-stratified studies with extended safety profiling are recommended before clinical adoption.