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.
The annual expenses for testosterone supplementation for a man with KS under these circumstances are currently around 2000 DKR (≈300 USD; 270 EURO). However, most prescription medications, including testosterone preparations for KS, are subject to own payment, but with a considerable public subsidy. Others argue that one should not start testosterone supplementation before serum total testosterone falls below normal ranges. Clinical practice in most countries has been that testosterone supplementation should be timed with the natural onset of puberty if testosterone production is inadequate and/or LH and follicle stimulating hormone rise above normal limits, which is the strategy that we use in our clinic (Gravholt et al., 2018). A review of the current KS literature yielded only a few studies which have focused on the impact of living with KS (Close, Fennoy, Smaldone, & Reame, 2015; de Ronde, de Haan, & Drent, 2009; Fjermestad & Stokke, 2018; Herlihy, McLachlan, et al., 2011; Skakkebaek, Moore, Chang, Fedder, & Gravholt, 2018; Turriff, Levy, & Biesecker, 2015). Although medical outcomes for patients with KS have been researched to some extent, the impact of living with KS has only been investigated sparsely. Although the oxandrolone protocol in prepubertal boys with KS tried to replicate normal physiology with consistent low-dose androgen exposure, nearly 25% of the boys Davis et al., 2018).
In November 2024, Nicklow's advocacy broadened when another TikTok video addressing potential bans on gender-affirming care, including testosterone shots, also went viral. This genetic condition affects individuals assigned male at birth, characterized by an extra X sex chromosome (XXY) instead of the typical XY. As a result, some of the body's cells have the usual one X chromosome and one Y chromosome (46,XY), and other cells have an extra copy of the X chromosome (47,XXY). Autoimmune disorders are a large group of conditions that occur when the immune system attacks the body's own tissues and organs. Affected individuals also have an increased risk for attention-deficit/hyperactivity disorder (ADHD), though they tend to have problems with attention and distractability rather than hyperactivity. Affected individuals have an increased risk for learning disabilities, most commonly problems with reading (dyslexia) and written expression.
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).
Recently, the effect of testosterone (or other androgen) treatment on body composition in individuals with KS has been evaluated in three placebo-controlled randomized trials in different age groups (Host et al., 2019). Also, typically in cross-sectional and uncontrolled studies, no change is seen in BMI after testosterone treatment in KS, possibly due to counter-balancing effects of fat loss and muscle build up (Bojesen, Kristensen, et al., 2006; Chang et al., 2015; Granato et al., 2019; Selice et al., 2013). As an example, in our most recent cross-sectional study, total body fat in testosterone-treated men with KS was 20% lower in treated compared with an age-matched group of untreated men with KS (Chang, Biltoft, et al., 2019).
In absence of a specific guideline for clinical management in KS, the way testosterone treatment is implemented is highly variable and dependent on clinician experience, patient preferences, and availability of formulation and possibly also insurer’s perception of the role of treatment, rather than on data-driven safety and efficacy. In regard to testosterone supplementation, a future guideline should also give specific aims for treatment in KS, preferably by evaluation of measurable predefined endpoints or intermediate endpoints, such as the level of luteinizing hormone (LH), testosterone, hemoglobin, bone mineral density, quality of life measures, libido, cognitive functioning, learning ability, and so on. There continues to be disagreement as to if testosterone treatment in the absence of hypergonadotropism, including boys with KS prior to and in early puberty, is clinically indicated.
In 1995, a scientific study evaluated the psychosocial adaptation of 39 adolescents with sex chromosome abnormalities. These neurocognitive disabilities are most likely due to the presence of the extra X chromosome, as indicated by studies carried out on animal models carrying an extra X chromosome. Compared to individuals with a typical number of chromosomes, males affected by Klinefelter syndrome may display behavioral differences. During puberty, KS subjects show less muscle mass, less facial and body hair, and broader hips as a consequence of low levels of testosterone. For example, patients with 49 chromosomes (XXXXY) have more extreme manifestations than those with 48 chromosomes (XXXY). Furthermore, a majority of hypogonadal KS patients were not treated with TRT. Although we assume that physicians only provided TRT to men who were found to be hypogonadal, this database does not allow us to draw the conclusion that all men treated with TRT were hypogonadal.
With or without testosterone treatment, thrombosis in boys and adolescents with KS is rare and in our anecdotal experience usually provoked (central line, orthopedic surgery, or other high risk circumstance). We are currently analyzing data from the same study, but also in a longitudinal setup, regarding effects of testosterone treatment in KS on fibrinolysis and platelet aggregation. In particular, the data indicate that testosterone treatment could attenuate the risk of venous thromboembolism in early adulthood, during which the relative risk of venous thromboembolism in KS compared with the background population is most pronounced (Chang, Christiansen, et al., 2019; Zoller et al., 2016).

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