In the following, we present a condensation of the available literature reporting health outcomes of testosterone treatment in KS in adults, and, when available in boys and adolescents. As such, major guidelines for testosterone treatment all agree that hypogonadism in men should be treated (Salter & Mulhall, 2019). "He will need testosterone replacement therapy when he is older since his body will produce low testosterone. Will he be denied his gender-affirming care?" "Gender-affirming care is just not for transgender youth," she explained, asserting that it would impact her son, who will require testosterone replacement therapy later in life due to low natural testosterone production. The global market for Klinefelter Syndrome therapeutics is significantly driven by advancements in hormonal therapy, which have broadened treatment options and bolstered confidence among healthcare professionals. 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. At the present time, clinicians with expertise in managing KS generally agree that testosterone treatment is beneficial for most men and adolescents with KS who have elevated luteinizing hormone and low (or low-normal) serum testosterone concentrations, although there are certainly those that think that testosterone levels should fall below the normative range before commencing therapy. As testosterone concentrations in an adolescent or young man with KS may still be in the low normal range although often with elevation of gonadotropin levels becoming evident, the criteria for initiating testosterone treatment given in most guidelines, for example, repeated low testosterone levels or symptoms of hypogonadism, represent a reactive approach that may lead to insufficient treatment in KS. However, these guidelines are not specific to the primary hypogonadism that is characteristic of KS, nor do they address hypogonadism and testosterone treatment during puberty. In the original publication describing KS, it is stated that "testosterone therapy is probably indicated," but the authors also reported little effect of high-dose testosterone treatment on the visual presentation of the index cases, particularly regarding the size of testes and gynecomastia (Klinefelter, Reifenstein, & Albright, 1942). We then identified a laboratory cohort by identifying men in the initial cohort who had received a testosterone laboratory measurement on the day of diagnosis of KS or later. We hypothesized that patients with diagnosed KS would be undertreated with TRT. In this study, we aimed to investigate the prevalence of hypogonadism in men with KS, and to describe the rates of TRT prescription among men with KS. Further studies are needed to corroborate these findings and to evaluate barriers to receiving care in this population. This duplicate chromosome can lead to small testicles and low to no testosterone production, which can affect physical development and fertility. But due to a random error, some boys are born with an extra copy of the X chromosome in each of their cells. Normally, girls are born with two X chromosomes, and boys are born with an X and a Y chromosome. Plunkett and Barr found the sex chromatin body in cell nuclei of the body. In 1956, Klinefelter syndrome was found to result from an extra chromosome. An approach by occupational therapy is useful in children, especially those who have dyspraxia. The use of behavioral therapy can mitigate any language disorders, difficulties at school, and socialization. If gynecomastia is present, the surgical removal of the breast may be considered for psychological benefits and to reduce the risk of breast cancer. As the genetic variation is irreversible, no causal therapy is available. Furthermore, Klinefelter syndrome can be diagnosed as a coincidental prenatal finding in the context of invasive prenatal diagnosis (amniocentesis, chorionic villus sampling). Also, there are indications of a positive effect of early testosterone supplementation on improving the behavioral phenotype in boys with KS (Samango-Sprouse et al., 2015), although these studies are purely observational and without proper randomization and inclusion of a placebo-treated control group of males with KS. In the study by Close et al. no association between quality of life and total testosterone level in blood were seen (Chang et al., 2015). To further understand the underlying cause of the decrement in quality of life seen in boys and men with KS, some of the studies investigated several variables that might be important predictors of quality of life. Overall, these studies unequivocally reported decreased quality of life or aspects of quality of life in boys, adolescents and adults with KS. As exemplified by a recent case presentation of prostatic cancer in a testosterone-treated man with KS (Nishikawa, Jia, Dharamshi, Charron, & Lock, 2019), there has been concern that treatment could increase the risk of prostatic cancer in men with KS. Future intervention studies should carefully assess the effect of testosterone on testicular function and the hypothalamic–pituitary axis in both prepubertal and postpubertal boys. Spermatogenesis requires high intratesticular testosterone stimulated by LH, therefore there is concern that testosterone treatment may reduce the success of fertility treatments in individuals with KS.
