Klinefelter Syndrome and Metabolic Disorder.

Hypogonadism is reported to be an independent risk factor for the development of central obesity in men, and epidemiologic studies indicate an inverse relation between serum testosterone and obesity [1]. In patients with prostate cancer, androgen deprivation therapies increased body fat mass [2], whereas it is known that androgen can prevent the differentiation of pluripotent cells into an adipogenic lineage [3]. Hypogonadism is also associated with metabolic syndrome and type 2 diabetes. Type 2 diabetes and metabolic syndrome are frequent in hypogonadal patients [14]. Cross-sectional studies have consistently reported an inverse relationship between plasma testosterone and insulin resistance in normal males [15]. Cessation of testosterone replacement therapy in patients with hypogonadism for 2 weeks reduced insulin sensitivity, indicating that testosterone itself has direct effects on insulin sensitivity [6]. Hypogonadism may lead to central obesity, increasing the risk of metabolic syndrome and the development of type 2 diabetes.

Hypergonadotropic hypogonadism is a key finding in Klinefelter syndrome, which is the most common sex chromosomal disorder in males [4]. Klinefelter syndrome patients have an unfavorable muscle/fat ratio with decreased muscle mass and increased total body and truncal fat accompanied by lower aerobic capacity and muscle strength [47]. Both epidemiological and clinical studies show clear evidence of a dramatically increased risk of diabetes and metabolic syndrome in Klinefelter syndrome [4]. Studies on Klinefelter syndrome have shown an increased risk of death due to diabetes or admission to a hospital with a metabolic disorder [89]. Hypogonadism in Klinefelter syndrome may cause an unfavorable change in body composition, increasing the risk of metabolic disorder [7].

In this issue of Endocrinology and Metabolism, Han et al. [10] found that the prevalence of obesity (defined by body mass index [BMI] ≥25 kg/m2) in Korean men with Klinefelter syndrome was 42.6% (160 of 376 patients). Based on the data acquired from the Korea National Health and Nutrition Examination Survey (KNHANES) in 2011, the prevalence of obesity (defined by BMI ≥25 kg/m2) in the Korean general population was 32.0% [11]. Considering this KNHANES data from the general population, prevalence of obesity in Korean patients with Klinefelter syndrome is greatly increased, as found in previous studies [410]. Additionally, in the current study, testosterone levels were negatively correlated with BMI and fasting glucose, which agrees with previous findings [1410]. Epidemiological studies on Klinefelter syndrome have been conducted mostly in Western cohorts, particularly in the British and the Danish populations [4]. The present study by Han et al. [10] with a large sample size was conducted in Asian patients, which make the findings in this study more valuable.

There is a close relationship between testosterone and insulin sensitivity or body composition [4]. Evidence from several studies has demonstrated that testosterone replacement therapy in hypogonadal men with obesity reduced body fat mass and increased insulin sensitivity [1]. However, available evidence does not support testosterone replacement therapy for Klinefelter syndrome patients for improving metabolic disorder. It is uncertain whether hypogonadal males and Klinefelter syndrome patients are comparable. Genetic factors related to Klinefelter syndrome might add another layer of complexity [4]. Thus, it is necessary to conduct a prospective study in hypogonadal obese insulin resistant patients with Klinefelter syndrome to clarify these issues.