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This consideration may partially explain the undertreatment of KS patients with TRT. First, the retrospective nature of our study may introduce incomplete or inaccurate capture of data. Hypogonadism poses a significant burden on the quality of life of men. A total of 1581 men (29.6%) received a laboratory measurement of their testosterone level on the day of diagnosis or later (Fig. 2). Descriptive analysis of comorbidities revealed 350 (6.5%) patients with a diagnosis of intellectual disability, 761 (14.2%) with type 2 diabetes mellitus, 995 (18.6%) with obesity, 919 (17.2%) with hypertension, 246 (4.6%) with osteoporosis, 757 (14.2%) with hyperlipidemia, 153 (2.9%) with history of pulmonary embolism, and 60 (1.1%) with a history of vascular thrombosis. There were in total 6071 men in the initial cohort with diagnosis of KS in the TriNetX database.
Additional investigation of the pathophysiology of the altered energy metabolism and long-term effect of androgen interventions is needed for boys and men with KS. It is possible that chronic hypogonadism results in metabolic memory that cannot be easily erased or reversed with short-term correction of hypogonadism and could be an argument for appointing more resources to minimizing the diagnostic lag-time among most with KS and thus the time spend in a hypogonadal state. The first was a 2-year, randomized, placebo-controlled trial of oral oxandrolone in 93 prepubertal boys 4–12 years of age (Ross et al., 2017).
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.
The median interquartile range (IQR) age at diagnosis among men with KS later treated with testosterone was 25.5 (15.3–34.3) years, but the median interquartile range (IQR) age at first testosterone prescription was 30.4 (19.2–40.9) years, indicating a delay of treatment of around 5 years. Although the current literature demonstrate a picture of patients with KS as suffering from poorer quality of life, and that the syndrome have severe implications for the majority of boys and men with KS, these patients seem to cope with their situation. There are important inherent ascertainment biases in the existing studies that may account for the lack of observing a beneficial effect of testosterone on quality of life outcomes and additional longitudinal investigation is warranted.
Individuals with Klinefelter syndrome typically have small testes that produce a reduced amount of testosterone (primary testicular insufficiency). Unauthorized use of these marks is strictly prohibited. The strongest associations were with body fat, indicating that metabolic dysfunction may be a key regulator of contact activation system activity. Contact activation system mediates crosstalk between coagulation, fibrinolysis, and inflammation and may contribute to thromboinflammatory risk. While hypogonadism and metabolic dysfunction are known contributors, the role of the contact activation system in Klinefelter syndrome remains unexplored.
To provide optimal care for boys and men with KS, it is required to establish specialized multidisciplinary clinics include a formalized structure ensuring seamless transition from pediatric to adult care. It is becoming increasingly clear that KS affects all aspects of life and that treatment of KS is demanding a multidisciplinary approach. However, recently we published nationwide data illustrating the use of testosterone among men with KS in Denmark (Chang, Christiansen, et al., 2019). We are confident that implementation of centralized interdisciplinary clinics not only improves overall care of men with KS, but could also be a means for addressing the diagnostic deficits by broadening awareness of KS and the nonendocrinological symptoms among a wider set of health care professionals. Care of KS in Denmark has in recent years been centralized at specialized endocrinology clinics at University Hospitals to offer care of males with KS across the entire lifetime.
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.
Theodore, diagnosed with Klinefelter Syndrome through genetic testing, is actively receiving early intervention services, including crucial speech therapy. Stephanie Nicklow is advocating for greater understanding of Klinefelter Syndrome by openly sharing her son Theodore's health journey. The information on this site should not be used as a substitute for professional medical care or advice. Similarly, if a sperm cell with both an X chromosome and a Y chromosome (XY) fertilizes an egg cell with a single X chromosome, the resulting child will have Klinefelter syndrome.
However, in our experience, most adult men with KS have overt hypogonadism at presentation and further, by including laboratory data from Danish hospitals, we were able to demonstrate biochemical signs of hypogonadism in those men with KS without testosterone prescriptions (Chang, Christiansen, et al., 2019). Two-thirds of responders agreed that the optimal timing for initiation of testosterone supplementation in KS was between 10 and 16 years of age, although there was no real consensus on whether to monitor testosterone levels, gonadotropin levels, or to look for clinical signs of delayed puberty or hypogonadism, to decide the actual timing of initiating treatment in the individual patient (Zganjar et al., 2019). However, the impact of testosterone supplementation on biological paternity in KS is still debatable, since others do not find that testosterone treatment impairs chances of fertility (Zganjar, Nangia, Sokol, Ryabets, & Samplaski, 2019).

Gender: Female