Endothelial progenitor cells as a new cardiovascular risk factor in Klinefelter's syndrome

Klinefelter syndrome (KS) is associated with a significant reduced life expectancy (2.1 years) including greater mortality from cardiovascular diseases. Underlying causes that may involve low levels of testosterone as well as the extra X chromosome are not fully understood. Low testosterone may have a direct affect on vascular tissue or act indirectly via metabolic effects. Testosterone levels may act genomically on cardiac function via the androgen receptor (AR) or non-genomically. Recently, it has been demonstrated that a reduced number of circulating endothelial progenitor cells (EPCs) is an independent predictor of morbidity and mortality from cardiovascular diseases. Because EPCs have never been studied in KS, we evaluated the number of circulating EPCs in 68 adult 47,XXY Klinefelter men and 46 healthy males. Patients and controls were divided into two groups, according to the absence or presence of cardiovascular risk factors (CRFs). Controls without CRFs had significantly higher levels of EPCs than controls with CRFs; on the contrary, KS patients without CRFs had EPCs levels similar to KS men with risk factors and significantly lower with respect to controls without CRFs. The number of EPCs in patients with hypogonadism was not different from that of those with normal testosterone levels. Twenty-two hypogonadal patients were re-evaluated after 6 months of androgen therapy, but we did not observe any modification in the number of EPCs. These primary hypothesis-generating data suggest that factors involved in KS, whether hypogonadism, CRFs or other genetically determined factors related to the supernumerary X chromosome might contribute to a reduction in EPCs number and that this could be considered another CRF contributing to the increased mortality of these subjects.