Scrotal Botulinum Toxin Exposure and Male Fertility: Mechanistic Insights and Clinical Evidence

Introduction: Scrotal botulinum toxin type A (BoNT-A) injections (“scrotox”) are increasingly used to relax the dartos and/or cremaster muscles for cosmetic purposes and for functional indications such as chronic scrotal pain/orchialgia, exaggerated cremasteric reflex, and cremasteric synkinesia. Evidence remains limited and dispersed across animal toxicology studies, urologic case reports, and pain-management trials. We conducted a systematic review to evaluate whether botulinum toxin exposure involving the scrotum, dartos, cremaster, spermatic cord/peritesticular region, or predefined regulatory male fertility datasets is associated with changes in male reproductive outcomes. Methods: We performed a systematic review in accordance with PRISMA 2020. PubMed/MEDLINE, Embase, and Scopus were searched from inception through January 5, 2026, with additional identification via reference screening and targeted retrieval of publicly available regulatory reproductive-toxicity documentation for onabotulinumtoxinA and prabotulinumtoxinA, the products for which relevant public regulatory datasets were available. Eligible studies included animal experiments and human clinical reports involving relevant anatomic exposure sites and reporting at least one fertility-relevant outcome (e.g., sperm parameters, spermatogenesis-related histology, reproductive hormones, or fertility indices). Given heterogeneity in exposure routes, dosing, and outcomes, meta-analysis was not planned; results were synthesized qualitatively. Risk of bias was assessed using SYRCLE (animal studies), Joanna Briggs Institute tools (case reports/series), and RoB 2.0 (randomized trials), and evidence levels were categorized using Oxford CEBM. Results: The search identified 93 records; after deduplication, 75 underwent title/abstract screening, 15 were reviewed in full text, and 10 studies met inclusion criteria for qualitative synthesis. Evidence was heavily weighted toward animal data. Animal studies provided moderate-quality evidence suggesting dose- and site-dependent reproductive effects: repeated or higher-dose exposures delivered adjacent to the testes (particularly intracremasteric administration) were associated with impaired spermatogenesis and adverse testicular histopathology, whereas very low-dose systemic intramuscular exposure distant from the testes was reported to be neutral or potentially beneficial in an ageing model. Human evidence was uniformly low or very low quality for fertility inference because published case reports, case series, and clinical trials primarily evaluated pain relief, neuromuscular outcomes, or cosmetic satisfaction and did not prospectively measure semen parameters, endocrine function, thermoregulatory metrics, or fertility endpoints. Conclusions: Current evidence is insufficient to determine the reproductive safety of scrotal or peritesticular botulinum toxin injections in humans. Preclinical data raise concern for potential spermatotoxicity with higher-dose and/or anatomically proximal exposure, while human studies remain indirect and lack fertility-specific monitoring. Standardized dosing and technique reporting, incorporation of semen and hormonal outcomes, direct thermophysiological assessment, and longitudinal follow-up are needed. Until such data exist, clinicians should counsel men desiring future fertility that mechanistic risk is plausible and definitive human fertility outcomes have not been established.