Development and Preliminary Clinical Evaluation of a Five-Item Prepubertal Risk Questionnaire for Severe...

Purpose: Severe spermatogenic impairment, including azoospermia, oligozoospermia, asthenozoospermia, and teratozoospermia, represents a major reproductive health concern, yet no validated screening tool exists for early risk stratification in prepubertal boys. We aimed to develop a five-item evidence-based questionnaire and conduct preliminary clinical evaluation to identify prepubertal boys at risk of developing severe spermatogenic impairment. Methods: This retrospective observational study analyzed medical records of 200 male patients aged 18 years who underwent their first semen analysis between 2014 and 2024 at the University of Catania, Italy. Prepubertal risk factor profiles were retrospectively reconstructed by two independent andrologists blinded to semen analysis results across five evidence-based domains: genetic anomalies (0-5 points), cryptorchidism (0-6 points), gonadotoxic cancer therapy (0-7 points), varicocele (0-4 points), and hormonal/endocrine disorders (0-5 points), yielding a total score of 0-27 points. Scoring weights were based on literature evidence and expert consensus. Reliability was assessed using Cronbach's α (n = 200), test-retest intraclass correlation coefficient (ICC, n = 30, 2-week interval), and inter-rater Cohen's κ (n = 50). Receiver operating characteristic (ROC) curve analysis identified optimal cut-offs. Semen analysis outcomes were classified according to WHO 2021 criteria. Results: The newly developed questionnaire demonstrated acceptable internal consistency (Cronbach's α = 0.81), good test-retest reliability (ICC = 0.89, 95% CI 0.84-0.93), and excellent inter-rater reliability (Cohen's κ = 0.87). Mean questionnaire scores showed a direct progressive correlation with severity of spermatogenic impairment. The highest scores were observed in azoospermia (mean 14), complete asthenozoospermia (13), and complete teratozoospermia (13). ROC curve analysis identified four clinically meaningful cut-offs: ≥6 (AUC = 0.85, 95% CI 0.79-0.91, Youden index = 0.81), ≥7 (AUC = 0.88, 95% CI 0.83-0.93, Youden = 0.80), ≥11 (AUC = 0.91, 95% CI 0.87-0.95, Youden = 0.79), and ≥13 (AUC = 0.94, 95% CI 0.90-0.97, Youden = 0.87). Four risk strata were defined: LOW (0-6), MEDIUM (7-10), HIGH (11-12), and VERY HIGH (≥13 points). Conclusions: The five-item prepubertal risk questionnaire undergoing preliminary clinical evaluation demonstrates strong correlation with subsequent spermatogenic outcomes, enabling early identification of at-risk boys. The four-tier stratification system provides actionable guidance for clinical management and fertility preservation counseling. However, this cohort was enriched for pathological outcomes due to exclusion of subjects with no known risk factors; cut-offs may not apply to general population screening. Multicenter validation studies in unselected populations are warranted.