The role of hypogonadism in Klinefelter Syndrome

Abstract

Klinefelter syndrome (KS) (47, XXY) is the most abundant sex-chromosome disorder, and is a common cause of infertility and hypogonadism in men. Most men with KS go through life without knowing the diagnosis, as only 25% are diagnosed and only a few of these before puberty. Apart from hypogonadism and azoospermia, most men with KS suffer from some degree of learning disability and may have various kinds of psychiatric problems. The effects of long-term hypogonadism may be difficult to discern from the gene dose effect of the extra X-chromosome. Whatever the cause, alterations in body composition, with more fat and less muscle mass and diminished bone mineral mass, as well as increased risk of metabolic consequences, such as type 2 diabetes and the metabolic syndrome are all common in KS. These findings should be a concern as they are not simply laboratory findings; epidemiological studies in KS populations show an increased risk of both hospitalization and death from various diseases. Testosterone treatment should be offered to KS patients from early puberty, to secure a proper masculine development, nonetheless the evidence is weak or nonexisting, since no randomized controlled trials have ever been published. Here, we will review the current knowledge of hypogonadism in KS and the rationale for testosterone treatment and try to give our best recommendations for surveillance of this rather common, but often ignored, syndrome.

Genetic Basis for Sex Differences in Obesity and Lipid Metabolism

“…Furthermore, Turner syndrome subjects often have congenital heart defects, which lead to heart disease independent of MetSyn (31). Individuals with Klinefelter syndrome (47, XXY) have reduced endogenous androgen levels and are often treated with exogenous androgens, which makes it difficult to distinguish effects of the XXY chromosome complement from those of the altered androgen levels (53). In addition to the factors outlined above, the interpretation of metabolic disease traits in Turner and Klinefelter subjects has been limited by small available cohort sizes that preclude meaningful conclusions about metabolic parameters.…”

DNA methylation signature in peripheral blood reveals distinct characteristics of human X chromosome numerical aberrations

“…Klinefelter syndrome, on the other hand, apart from phenotypic features, such as high stature, gynecomastia, and infertility, is often linked to declined verbal skills [ 7 ]. Both syndromes have the hallmark characteristic of abnormal endocrine balance and display hypergonadotropic hypogonadism [ 8 – 10 ]. The details of the underlying molecular mechanisms that lead to the development of these symptoms associated with X chromosome abnormalities are poorly understood.…”

A rare variety of congenital adrenal hyperplasia with mosaic Klinefelter syndrome: a unique combination presenting with ambiguous genitalia and sexual precocity

“…Phenotypic heterogeneity is a significant feature of KS, while its manifestations can be attributed either to the aneuploidy and the impact of increased gene dosage by the supernumerary X or the presence of hypogonadism per se ( 15 ). Though premature failure of Leydig cell function is observed in KS subjects, hypogonadism is usually not evident before early adulthood ( 16 ). In line with this, congenital anomalies of the genital organs driven by hypogonadism such as micropenis, bifid scrotum or hypospadias, although more frequent in KS than in the general population, have an overall low prevalence ( 17 ).…”