Higher testosterone level is associated with improved cognitive functions in Klinefelter syndrome

Abstract Klinefelter syndrome (KS) is a common sex chromosome aneuploidy affecting one to two per 1000 live male births. Testosterone therapy and neuropsychological support can enhance the quality of life in affected individuals. While cognitive deficits have been documented in Klinefelter syndrome, the influence of hormonal variability on cognitive profiles remains underexplored. This study aimed to determine whether testosterone levels correlate with neurocognitive functions in Klinefelter syndrome individuals. This cross‐sectional study involved a heterogeneous clinical sample from a single tertiary referral hospital. Participants: Thirty Klinefelter syndrome individuals were enrolled, being 21 with 47, XXY without neurological comorbidities, aged 17–65 years. Participants underwent blood tests for total testosterone, free testosterone, estradiol, sex‐hormone‐binding globulin, follicle‐stimulating hormone, luteinizing hormone, and anti‐Müllerian hormone. A comprehensive neuropsychological assessment was also conducted, covering intellectual quotient (Wechsler Scale) and higher‐order cognitive functions (attention, executive functions, language, memory, and visuoconstructional abilities). Neuropsychological performance was notably better in Klinefelter syndrome individuals with higher levels of testosterone. Spearman's test revealed significant correlations between total testosterone, free testosterone, and gonadal status measured by free testosterone/luteinizing hormone and free testosterone/estradiol ratios and cognitive flexibility tasks. The mean age of participants was 33.1 years (SD = 14.0), and free testosterone/luteinizing hormone and free testosterone/estradiol measures were correlated with set‐shifting, verbal memory, visual functions, and adaptive behavior domains, including communication, daily living, and motor skills. The free testosterone:estradiol ratio was also consistently associated with total intellectual quotient, verbal comprehension, perceptual organization, and processing speed indexes. The study highlights the positive correlation between testosterone levels and cognitive functions in Klinefelter syndrome males. These insights reinforce the role of testosterone in neurocognitive development, suggesting the potential benefits of testosterone therapy in managing cognitive deficits in Klinefelter syndrome. More extensive confirmatory studies are necessary to substantiate these findings and to explore the mechanisms involved.