Total osteocalcin levels are independently associated with worse testicular function and a higher degree of hypothalamic-pituitary-gonadal axis activation in Klinefelter syndrome.

Total osteocalcin (tOCN) levels varied throughout the lifespan according to pubertal status in Klinefelter syndrome patients.

• The study included 254 male patients with KS (47,XXY) followed between 2007 and 2021 at an academic referral center.
• Patients were categorized as prepubertal, pubertal, and adults.
• tOCN levels were highest in eugonadal adult patients and significantly lower in those receiving testosterone replacement therapy (TRT).
• The retrospective longitudinal study design allowed comparison across different stages of pubertal development.

In adult KS patients, tOCN levels correlated positively with LH and FSH levels.

• tOCN correlated with LH levels (p = 0.017) in adult KS patients.
• tOCN correlated with FSH levels (p = 0.004) in adult KS patients.
• These correlations indicate an association between higher osteocalcin and greater hypothalamic-pituitary-gonadal axis activation.
• No such correlations with HPG-axis hormones were found in prepubertal boys.

After adjustment for age and BMI, tOCN showed significant inverse correlations with testosterone-related parameters in adult KS patients.

• Significant inverse correlation was found between tOCN and total testosterone (p = 0.004).
• Significant inverse correlation was found between tOCN and calculated free testosterone (p = 0.016).
• Significant inverse correlation was found between tOCN and the testosterone/LH ratio (p = 0.010).
• Significant inverse correlation was found between tOCN and the calculated free testosterone/LH ratio (p = 0.031).
• These results indicate that higher tOCN is associated with worse testicular function as reflected by lower testosterone and lower testosterone-to-LH ratios.

Testosterone replacement therapy significantly reduced tOCN levels within 3 months in adult KS patients.

• 18 adult KS patients had available tOCN levels both before and 3 months after TRT commencement.
• tOCN levels significantly declined after 3 months of TRT (p = 0.006).
• This finding suggests an acute suppressive effect of exogenous testosterone on osteocalcin production.
• TRT subjects had significantly lower tOCN levels compared to eugonadal adult KS patients.

tOCN levels were not associated with gonadal function during prepuberty and pubertal development in KS.

• All prepubertal patients included in the study were testosterone-naïve.
• HPG-axis hormone levels demonstrated no correlation with tOCN in prepubertal boys.
• This suggests the bone-gonadal axis relationship via osteocalcin is not operative during normal prepubertal development in KS.
• The dissociation between prepubertal and adult findings indicates that the association of tOCN with testicular function is an adult phenomenon in this condition.

The study investigated the role of osteocalcin in the context of Klinefelter syndrome as a model of adult hypergonadotropic hypogonadism.

• KS (47,XXY) was used as a clinical model of adult hypergonadotropic hypogonadism.
• Adult patients were subcategorized as eugonadal, hypogonadal, and receiving TRT.
• The role of OCN in pubertal development, male hypogonadism, and the effect of TRT was described as unclear prior to this study.
• The study was conducted at an academic referral center spanning 2007 to 2021.