Osteoporosis and bone metabolism in patients with Klinefelter syndrome

: Low bone mass is common in men with Klinefelter syndrome (KS), with a prevalence of 6-15% of osteoporosis and of 25-48% of osteopenia. Reduced bone mass has been described since adolescence and it might be related to both reduced bone formation and higher bone resorption. Although reduced testosterone levels are clearly involved in the pathogenesis, this relation is not always evident. Importantly, fracture risk is increased independently from bone mineral density (BMD) and testosterone levels. Here we discuss the pathogenesis of osteoporosis in patients with KS, with a particular focus on the role of testosterone and testis function. In fact, other hormonal mechanisms, such as global Leydig cell dysfunction, causing reduced Insulin-like factor 3 (INSL3) and 25-OH vitamin D levels, and high FSH and estradiol levels, might be involved. Furthermore, genetic aspects related to the supernumerary X chromosome might be involved, as well as androgen receptor expression and function. Notably, body composition, skeletal mass and strength, and age at diagnosis are other important aspects. Although Dual-Energy X-ray Absorptiometry (DXA) is recommended in the clinical workflow for patients with KS to measure BMD, recent evidence suggests that alterations in the microarchitecture of the bones and vertebral fractures might be present even in subjects with normal BMD. Therefore, analysis of trabecular bone score (TBS), high resolution peripheral quantitative CT and vertebral morphometry seem promising tools to better estimate the fracture risk of patents with KS. This review also summarizes the evidence on the best available treatments for osteoporosis in men with KS, with or without hypogonadism

Negative Association Between Sclerostin and INSL3 in Isolated Human Osteocytes and in Klinefelter Syndrome: New Hints for Testis-Bone Crosstalk

The regulation of bone mass by the testis is a well-recognized mechanism, but the role of Leydig-specific marker insuline-like 3 peptide (INSL3) on the most abundant bone cell population, osteocytes, is unknown. In this study we aimed to investigate the relationship between INSL3 and Sclerostin, an osteocyte-specific protein that negatively regulates bone formation

Estradiol-Testosterone Imbalance Is Associated with Erectile Dysfunction in Patients with Klinefelter Syndrome

Erectile dysfunction (ED) is a frequent sexual disorder in adult men. Klinefelter syndrome (KS) is the most common sex chromosomal disorder and a frequent cause of male hypogonadism. Psychological and cognitive aspects are quite typical in KS and have been linked to ED, while the role of testosterone (T) levels in sexual function of KS subjects has not been fully elucidated. The purpose of the present study is to investigate the role of hormonal disturbances in erectile function of subjects with KS. We conducted a retrospective study involving 52 Klinefelter patients newly diagnosed who never received androgen replacing therapy. All the subjects underwent medical history, accurate physical examination, and blood tests. The International Index of Erectile Function questionnaire (IIEF-EF) score correlated negatively with estradiol/testosterone ratio (E2/T); this correlation remained statistically significant after correction for age (ρ −0.320 p = 0.018). A multiple linear regression analysis identified age and E2/T as the main predictors of IIEF-EF score (R2 0.169 F = 3.848 p = 0.008). Our findings corroborate previous KS data obtained in the general population showing an association between higher E2/T ratio and impaired erectile function. Larger studies are required to better elucidate the pathophysiology of ED in patients with KS