Purpose: Klinefelter syndrome (KS), the most common sex chromosome aneuploidy in males, is frequently associated with hypogonadism and metabolic dysfunction during adolescence and adulthood. However, data on the early endocrine and metabolic phenotype of prepubertal individuals with KS remain limited. This study aimed to descriptively characterize reproductive hormone profiles and metabolic parameters in prepubertal boys with 47,XXY KS and to explore early endocrine–metabolic associations across developmental stages.

Methods: A retrospective cross-sectional analysis was conducted on 40 prepubertal boys with confirmed 47,XXY karyotype, aged 0.6–10.0 years. Anthropometric, biochemical, and hormonal data were collected. Participants were stratified into three age groups: < 2, 2–5, and > 5 years. Statistical analyses included Kruskal–Wallis and Mann–Whitney U tests, Spearman correlations, and multiple linear regression models adjusted for age and body mass index.

Results: Age-related increases in luteinizing hormone, inhibin B, and testosterone suggested early activation of the hypothalamic–pituitary–gonadal axis. Although most metabolic parameters fell within pediatric reference ranges, 27.5% of participants had high-density lipoprotein (HDL) cholesterol < 40 mg/dL, 17.5% had elevated triglycerides, and 5.0% exhibited insulin resistance (homeostatic model assessment for insulin resistance (HOMA-IR) > 2.5). HDL levels rose and triglycerides declined with age. Testosterone was positively associated with insulin and HOMA-IR. While the regression model predicting HDL was significant, no single hormone emerged as an independent predictor.

Conclusions: Prepubertal boys with 47,XXY KS may exhibit early hormonal changes and subtle metabolic alterations. These findings support the importance of early endocrine and cardiometabolic surveillance, even before the onset of clinical puberty.