Low INSL3 in Klinefelter syndrome is related to osteocalcin, testosterone treatment and body composition, as well as measures of the hypothalamic-pituitary-gonadal axis

Klinefelter syndrome (KS) is characterized by infertility and hypogonadism associated with increased prevalence of osteoporosis, diabetes and metabolic syndrome. Insulin-like factor 3 (INSL3) is produced in the Leydig cells. INSL3 has been suggested to play a role in bone health. Here, we studied INSL3 in relation to bone markers, body composition, the metabolic syndrome and diabetes. This was a case-control study. Sex hormones, anthropometric measures, vitamin D metabolites, parathyroid hormone, growth factors, muscle strength, maximal oxygen consumption and BMD were measured. We included 70 adult KS patients and 71 age-matched controls. INSL3 was lower in testosterone-treated KS compared with untreated KS. Correlation analyses showed a positive correlation between INSL3 and osteocalcin among KS, but not in controls; a significant positive correlation between INSL3 and testosterone in controls and in untreated KS, but not in treated KS men. Among controls a negative correlation was found between INSL3 and lipids, and glucose, but not in KS. HOMA2-B and impaired fasting glycaemia was positively correlated with INSL3 in controls. Among KS males we found a negative correlation between INSL3 and BMI, weight and waist/hip ratio, as well as positive correlations between INSL3 and FSH, LH, SHBG and testis volume. Multivariate analyses showed that age, testosterone and HDL cholesterol were the principal independent variables among healthy controls, whereas the determinants of INSL3 concentration among KS were age, LH, current testosterone treatment and testicular volume. INSL3 in KS is influenced by testosterone treatment and INSL3 is correlated with measures of bone metabolism, body composition and the metabolic syndrome. This may suggest that low INSL3 concentration is related to the pathogenesis behind an unfavourable change in body composition and bone metabolism among KS patients.