New insights needed to improve fertility outcomes in patients with Klinefelter syndrome

In this interview, Leila Momtazi-Mar, of Cleveland Clinic Lerner College of Medicine in Cleveland, highlights major knowledge gaps and future research priorities in fertility preservation for individuals with Klinefelter syndrome (KS).¹

She emphasizes that significant age-related uncertainties remain, particularly the absence of studies involving patients aged 20 to 24 years—a period that may represent an optimal window for sperm retrieval. Likewise, there are limited data on men over 40 years of age, leaving unclear how advancing paternal age affects retrieval success. Addressing these gaps with targeted studies could clarify whether young adulthood offers higher or comparable retrieval rates relative to older age groups.

Another critical research need involves understanding the effects of exogenous testosterone. Although testosterone therapy is widely known to suppress spermatogenesis, its specific impact in KS—especially when administered during adolescence for virilization—has not been rigorously evaluated. This includes determining whether hypogonadal patients with KS who naturally virilize truly benefit from testosterone therapy and how such treatment influences later sperm retrieval outcomes.

Momtazi-Mar also notes substantial variability in surgical and laboratory techniques across studies. Future work should compare outcomes using fresh vs cryopreserved sperm, assess the role of fine-needle aspiration, and standardize procedural pathways to better interpret results across centers. Beyond biological and technical factors, she stresses the importance of patient-centered outcomes. The psychological consequences of delaying retrieval until adulthood, as well as the potential emotional impact of a positive or negative retrieval during adolescence, warrant further investigation to support holistic, informed decision-making.

For clinicians counseling patients with KS, Momtazi-Mar underscores several key messages. First, sperm retrieval can be safely deferred until adulthood; adolescence is not required. Second, patients must receive realistic guidance about outcomes, as median live-birth rates remain low—around 11% in reviewed studies. Third, although age over 40 may influence retrieval rates, current evidence is limited and should be presented with appropriate nuance. Finally, hormonal levels should not be treated as predictive determinants of retrieval success; instead, they serve mainly as contextual clinical information.

Overall, she advocates multidisciplinary, shared decision-making to help each patient choose the most appropriate timing for fertility treatment.

REFERENCE

1. Momtazi-Mar L, Naelitz BD, Mucci A, Cannarella R, Lundy SD. Surgical sperm retrieval in patients with nonmosaic Klinefelter syndrome (47,XXY) may be safely delayed until adulthood: a systematic review and meta-analysis. Fertil Steril. 2025 Jul 19:S0015-0282(25)00594-1. doi:10.1016/j.fertnstert.2025.07.021