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

Abstract

Purpose: The role of osteocalcin (OCN) in pubertal development, male hypogonadism, and the effect of testosterone (Te) replacement therapy (TRT) remains unclear. We aimed to investigate the total OCN (tOCN) concentrations in male patients with Klinefelter syndrome (KS), a model of adult hypergonadotropic hypogonadism.

Methods: This retrospective longitudinal study investigated 254 male patients with KS (47,XXY) between 2007 and 2021 at an academic referral center, categorized as (1) prepubertal, (2) pubertal, and (3) adults. All prepubertal patients were Te-naïve. Adult patients were subcategorized as (1) eugonadal, (2) hypogonadal, and (3) receiving TRT. We also analyzed 18 adult patients with available tOCN levels before and 3 months after TRT commencement.

Results: The tOCN levels varied throughout the lifespan according to pubertal status, were highest in eugonadal and significantly lower in TRT subjects, correlated with both LH (p = 0.017) and FSH levels (p = 0.004) in adults, and significantly declined after 3 months of TRT (p = 0.006) in the adult KS cohort. HPG-axis hormones levels demonstrated no correlation in prepubertal boys. Adjustment for age and body mass index confirmed previous results and revealed significant inverse correlations with total Te (p = 0.004), calculated free Te (p = 0.016), the Te/LH (p = 0.010), and calculated free Te/LH ratios (p = 0.031).

Conclusion: In KS, a model of male hypergonadotropic hypogonadism, tOCN levels were not associated with gonadal function during normal prepuberty and pubertal development but were associated with worse testicular function and a higher degree of HPG stimulation in adults. TRT acutely reduced tOCN levels in adults.

Keywords: Bone; Bone-testicular axis; Gonadotropins; Klinefelter syndrome; Osteocalcin; Testis; Testosterone.

Fig. 1

Total osteocalcin levels according to pubertal, gonadal, and TRT status in subjects with KS. Data are visually represented with box–whisker plots as the median (black lines), 25–75% IQR (boxes), and 2.5th–97.5th percentiles (whiskers), and with a before–after plot (panel C). tOCN values in subjects with KS are presented according to pubertal (panel A), gonadal (panel B), and TRT status (panels B and C). A number of subjects for each subgroup, according to pubertal status: prepubertal (n = 48), pubertal (n = 46), adult (n = 160). B number of adult subjects, according to gonadal status: eugonadal (n = 47), hypogonadal (n = 39), those receiving TRT (n = 74). C number of subjects in the pre- / post-TRT subgroups (n = 18). *p < 0.05, **p < 0.01, ***p < 0.001, ns = not significant. KS Klinefelter syndrome, tOCN total osteocalcin, TRT testosterone replacement therapy

Fig. 2

Total osteocalcin correlations with gonadotropins’ levels in adult subjects with KS Pearson’s coefficients and the respective p-values are shown for LH (panel A) and FSH (panel B). Subjects undergoing TRT are shown as red circles, whereas subjects not undergoing TRT are shown as blue boxes. A and B, number of subjects included in the analyses, n = 160. tOCN total osteocalcin