This includes established testosterone replacement therapies, assisted reproductive technologies, and a promising pipeline of targeted hormonal and genetic interventions. However, it is estimated that only 25% of the individuals with Klinefelter syndrome are diagnosed throughout their lives. A 2024 study showed 19% of KS respondents identified as intersex or non-binary, 12% as female and 53% as male, with 56% overall noting some discrepancy between their gender identity and their physical appearance. In August 2022, a team of scientists published a study of a skeleton found in Bragança, north-eastern Portugal, of a man who died around 1000 AD and was discovered by their investigations to have a 47,XXY karyotype. Jacobs described her discovery of this first reported human or mammalian chromosome aneuploidy in her 1981 William Allan Memorial Award address. As such there is no solid evidence suggesting that normalization of testosterone levels in men with KS would increase the risk of prostatic cancer above the rates seen among non-KS men. However, gonadotropins and testicular function hormones (Inhibin B, testosterone, and anti-Müllerian hormone) were not significantly different between treated and untreated groups when adjusted for pubertal status. In prepubertal boys, exogenous sex hormones may prematurely lift the breaks on the otherwise quiescent hypothalamic–pituitary– gonadal axis, potentially triggering early activation as seen in some conditions with chronic sex steroid exposure such as congenital adrenal hyperplasia. Other pediatric studies in KS have not evaluated bone density, but epiphyseal maturation is also an important endpoint for boys who are still growing. See a listing of all our Children’s Hospital Colorado locations including inpatient, outpatient, therapy, surgery facilities and more. In life-threatening emergencies, find the emergency room location nearest you. Of course, nontreatment could be a personal preference, due to, for instance, a lack of disease awareness or fears of adverse effects. We consider it surprising that there is such a low rate of treatment in the entire Danish cohort of men with KS and such a relatively long delay before initiation of treatment. Similar approaches are being implemented outside of Denmark (Salzano et al., 2016; Tartaglia et al., 2015) with the establishment of specialized KS clinics for both boys (Tartaglia et al., 2015) and men (Kalia, 2019) with KS. In the specialized centers all relevant medical specialties are represented and there is also a procedure for securing transition from pediatric to adult care. The impact of testosterone treatment on quality of life in patients with KS has not been investigated sufficiently. While additional studies with large samples sizes are needed, there is no clear evidence suggesting that testosterone treatment should be withheld in hypogonadal individuals due to the risk of thrombosis. Available studies have mainly focused on the risk of myocardial infarction in the setting of testosterone supplementation, but registry data from UK have also indicated a potential increased risk of venous thromboembolisms 3–6 months after initiation of testosterone treatment in hypogonadal men (Martinez et al., 2016). Most find no effect of testosterone treatment on levels of total cholesterol or LDL cholesterol while two cross-sectional studies report higher triglycerides in treated KS (Chang et al., 2015; Jorgensen et al., 2015) and four cross-sectional studies reporting decreased HDL in treated KS (Aksglaede et al., 2011; Chang et al., 2015; Jorgensen et al., 2015; Zitzmann et al., 2015). Nobody discussed issues such as a probable effect of testosterone supplementation on learning ability and betterment of neurocognitive abilities. In recent years there has been a growing focus on potential beneficial effects of testosterone supplementation in prepubertal boys (Davis et al., 2017; Ross et al., 2017). We find that in Denmark, the most common reason for delay of treatment after diagnosis is fertility treatment. Because of the lack of consensus guidelines there are not specific criteria for testosterone supplementation in KS, and perhaps most importantly when treatment should commence. In contrast to phenotypic severity, higher level of education were found to correlate positively with quality of life (3), whereas poor sleep affected quality of life negatively (Fjermestad & Stokke, 2018). Herlihy, McLachlan, et al. (2011) also reported phenotypic severity as the strongest predictors of all outcomes in adults with KS, although employment status and social support also influenced quality of life. In a previously published study, 75% of KS participants answered that the syndrome had significant negative consequence on their life. As such, adherence to testosterone treatment could have a secondary effect on risk of diabetes and diabetes control and by that potentially quality of life and mortality. As an example, the effects of testosterone treatment on metabolism seem to be more pronounced in men with idiopathic hypogonadotropic hypogonadism compared with men with KS (Jiang-Feng et al., 2012), although direct head-to-head studies comparing similar dose and duration of testosterone replacement therapy in males with KS and other groups of hypogonadal men have not been performed. Despite the apparent need to treat hypogonadism with testosterone in individuals with KS, there are relatively few studies directly addressing the health effects of treatment, and most of these studies are cross-sectional or uncontrolled longitudinal studies. There are no widely implemented guidelines for KS care, and studies investigating crucial aspects of testosterone treatment in individuals with KS, including both beneficial and potentially adverse effects, have only begun to emerge during the last decades. The condition leads to hypergonadotropic hypogonadism and ever since the condition was described approximately 80 years ago, testosterone treatment has been the cornerstone in care for individuals with KS. In this retrospective epidemiological study, we found that men with a diagnosis of KS are undertreated with TRT despite the recommendation for lifelong testosterone replacement after puberty in this population.
