Building on their pilot, the current research hypothesized that testosterone injections during the mini puberty period would offer short-term physical, hormonal and neurodevelopmental benefits to infants with XXY. Clinical features of XXY may be attributed to inadequate testosterone during this "mini-puberty" period of infancy. Hallmarks of XXY include impaired testicular function, infertility and differences in physical growth, metabolism and neurodevelopment, leading to increased morbidity and mortality. As cell-free DNA screening during pregnancy becomes standard, clinicians are increasingly identifying sex chromosome aneuploidies (variations) in infants.
We are especially interested in further study into other problems that men with KS face such as sexual dysfunction. In a large cohort of 5347 patients with KS, only 27.8% subsequently received TRT. It is possible that men who were asymptomatic were less likely to receive treatment with TRT even if they were hypogonadal by laboratory assessment.
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.
However, in our recent cohort study assessing prescription medicine, men with KS on testosterone therapy were twice as likely to also receive prescriptions for antihypertensive medications compared with those men with KS not redeeming testosterone prescriptions (Chang, Christiansen, et al., 2019). However, typically blood pressure in KS is within the normal range (Gravholt et al., 2018), and whether any effect of testosterone treatment on blood pressure would be clinically relevant seems unlikely. We believe this phenomenon, rather than being an effect of selection bias, is due to an overall higher standard of care in KS patients attending specialized clinics, thus leading to males being appropriately diagnosed with diabetes and receiving relevant treatment. It is likely the effect of testosterone treatment on insulin sensitivity would be secondary to loss of fat mass and increased muscle mass, rather than direct effects on glucose metabolism. In contrast, a previous uncontrolled study of 56 men with KS demonstrated a significant reduction in HOMA-IR after 18 months of treatment with testosterone gel (Selice et al., 2013).
The global Klinefelter Syndrome therapeutics market faces significant challenges due to a lack of awareness about the condition among healthcare providers, which leads to delays in diagnosis and referrals to specialists. Global klinefelter syndrome therapeutics market is segmented by treatment type, route of administration (trt), clinical focus, end-user and region. Because of (primary) hypogonadism, individuals often have a low serum testosterone level, but high serum follicle-stimulating hormone and luteinizing hormone levels, hypergonadotropic hypogonadism. In particular, research exploring the psychological, social, and socioeconomic considerations in management of patients with KS could shed light on important underlying mechanisms for underdiagnosis and undertreatment in this population. Patients with KS may experience various degrees impairment in language and executive function (concept formation, problem-solving, and task switching).14 An impaired self-awareness and learning difficulties exhibited in some KS patients could potentially lead to limited recognition of the signs and symptoms of hypogonadism, although it remains to be seen if this reliably translates to a lack of capacity to recognize symptoms of hypogonadism.15 Without strong family or social support, patients with KS may be less able to seek evaluation or treatment for their condition.
Treatment with exogenous testosterone suppresses the endogenous hypothalamic–pituitary–gonadal axis in post-pubertal males. Boys treated with oxandrolone experienced advanced bone age even with safety stopping and dose-reduction criteria in place (Davis et al., 2017). We conducted a cross-sectional study using high-resolution peripheral Quantitative Computed Tomography scanning of tibia and radius enabling a view of the microarchitecture of both trabecular and cortical bone. Several cross-sectional studies have documented decreased bone mineral density among men with KS in comparison with controls during a broad age range (Bojesen et al., 2011; Ferlin et al., 2011; van den Bergh et al., 2001). Hypogonadism is in itself linked to reduced bone mineral density, thus leading to an increased risk of fractures and osteoporosis.
It is also possible that men with a diagnosis of KS followed up for clinical workup and subsequent TRT prescription at a health care organization that does not report data to the TriNetX database, potentially leading to underestimation of the true rate of treatment with TRT in this cohort. Furthermore, this study lacks data on clinical follow-up, so we are unable to assess whether or not these men were undertreated due to the fact that they did not follow up with a specialist to discuss their diagnosis or laboratory results and receive TRT. This consideration may partially explain the undertreatment of KS patients with TRT.To our knowledge, this study is the first to describe the rates of TRT prescription in men with KS, and is one of few studies in the literature to objectively describe the prevalence of hypogonadism in patients with KS in a large patient population. Most individuals lacked a comprehensive understanding of the use and health benefits of testosterone treatment. There are few longitudinal or randomized studies investigating health-related outcomes of testosterone treatment in KS, but the available evidence stemming from mostly cross-sectional studies indicate beneficial effects of testosterone treatment on factors contributing to the excess morbidity burden and mortality seen in adult KS.
We hypothesized that men with KS are under-treated for testosterone deficiency with TRT due to a combination of factors, including a poor understanding of hypogonadism in this population and neurocognitive issues leading to delay in seeking of treatment for hypogonadism. The objective of this study was to determine the rates of hypogonadism and prescription of testosterone replacement therapy (TRT) in men with Klinefelter syndrome (KS). Such studies are needed to address issues such as timing of testosterone supplementation, different modalities of treatment and how to best monitor treatment and would be of high value in creating an evidence and consensus based guideline for care in KS.

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