NEW real-world evidence from a large multicentre Italian cohort suggests that baseline serum testosterone levels and testicular histology can meaningfully predict the likelihood of successful sperm retrieval in men with nonmosaic Klinefelter syndrome undergoing testicular sperm extraction (TESE).
The study analysed clinical outcomes from 383 men with nonmosaic Klinefelter syndrome and nonobstructive azoospermia treated at 12 tertiary referral centres across Italy between 2008 and 2024. Prior to surgical intervention, all patients underwent comprehensive preoperative evaluation, including hormonal profiling, genetic confirmation, and imaging assessments. Participants subsequently underwent either conventional TESE or microsurgical TESE, reflecting real-world practice across specialised centres.
Real-World Sperm Retrieval Outcomes
Overall, sperm retrieval was successful in 29.8% of patients, highlighting that despite severe testicular dysfunction, a clinically meaningful proportion of men with nonmosaic Klinefelter syndrome retain focal spermatogenesis. Men with positive sperm retrieval had modestly but significantly higher baseline total testosterone levels compared with those in whom retrieval was unsuccessful, suggesting a link between preserved Leydig cell function and residual spermatogenic activity.
Approximately two-thirds of the cohort underwent conventional TESE, with the majority of procedures performed bilaterally. While the study was not primarily designed to compare surgical techniques, the findings reinforce that both conventional and microsurgical approaches can yield sperm in selected patients when performed in experienced centres.
Histology as a Key Predictor
Testicular histology emerged as one of the strongest determinants of sperm retrieval success. Sertoli cell-only syndrome was predominantly associated with failed retrieval, reflecting widespread seminiferous tubule dysfunction in this subgroup. In contrast, hypospermatogenesis was strongly linked to positive outcomes, underscoring the prognostic importance of identifying preserved spermatogenic architecture.
In multivariable analysis, both higher baseline total testosterone levels and the presence of hypospermatogenesis independently predicted successful sperm retrieval. These findings highlight the biological heterogeneity within nonmosaic Klinefelter syndrome and challenge the perception of uniformly irreversible testicular failure.
Implications for Personalised Counselling
The results support a more individualised approach to fertility counselling in men with nonmosaic Klinefelter syndrome. Incorporating baseline hormonal profiles alongside histological data can help clinicians provide clearer, evidence-based counselling regarding the probability of success before patients undergo invasive surgical procedures.
The authors conclude that combining endocrine and histopathological markers offers clinically meaningful guidance for managing fertility expectations in this complex patient population. Importantly, these predictors may also help identify patients with a very low likelihood of sperm retrieval, potentially avoiding unnecessary surgery, reducing procedural burden, and supporting more informed, patient-centred reproductive decision-making.
Reference
Raffo M et al. Serum total testosterone and testicular histology help predicting positive sperm retrieval in nonmosaic Klinefelter patients undergoing testicular sperm extraction: real-life data from a large multicenter cohort. Fertil Steril. 2026;125(1):45–53.
