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Morbidity in Klinefelter syndrome and the effect of testosterone treatment.

ABSTRACT: Klinefelter syndrome (KS; 47,XXY) is the most common sex chromosome abnormality in males (150 per 100,000 males). 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. However, KS is associated with an array of health-related and socioeconomic challenges and it is becoming progressively clear that proper care for boys and men with KS reaches far beyond simply supplementing with testosterone. 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. For this descriptive review, we present an overview of literature describing health-related outcomes of testosterone treatment in KS and outline the clinical applications of testosterone treatment in KS. Collectively, beneficial effects of testosterone treatment on overall health in KS are described with few apparent adverse effects. However, larger randomized studies in adult and pediatric patients are warranted to elucidate key aspects of treatment. We stress the implementation of centralized multidisciplinary clinics and the need for a dedicated international guideline to ensure optimal care of boys and men with KS.

SUBMITTER: Chang S

PROVIDER: S-EPMC7413637 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Morbidity in Klinefelter syndrome and the effect of testosterone treatment.

Chang Simon S Skakkebaek Anne A Davis Shanlee M SM Gravholt Claus H CH

American journal of medical genetics. Part C, Seminars in medical genetics 20200604 2

Klinefelter syndrome (KS; 47,XXY) is the most common sex chromosome abnormality in males (150 per 100,000 males). 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. However, KS is associated with an array of health-related and socioeconomic challenges and it is becoming progressively clear that proper care for boys and men with KS reaches far ...[more]

PMID: 32496001

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Project description:IntroductionKlinefelter syndrome (KS) is a genetic condition characterised by the presence of an extra X chromosome in males (47,XXY). KS is associated with various phenotypic characteristics in adult life, including infertility, hypogonadism and increased risk of type II diabetes, cardiovascular disease and osteoporosis. Additionally, individuals with KS often experience mental health challenges and functional impairments that significantly impact their quality of life. Currently, testosterone replacement therapy (TRT) in adolescence is considered the first-line treatment by some physicians for patients with KS and biochemical signs of hypogonadism. However, comprehensive evidence on its effectiveness in preventing typical phenotypic traits associated with KS remains limited, and, currently, no evidence-based recommendations for TRT in this population exist. We therefore aim to evaluate the effects of two years of TRT during puberty in boys with KS. The primary endpoint is to monitor changes in body fat percentage. Secondary endpoints include changes in pubertal development and virilisation, growth and body proportions, bone mineralisation, muscle strength, lipid and glucose metabolism, systemic inflammation, methylation, fertility and effects on the cognitive and psychopathological features of KS.Methods and analysisThe TIPY study is a multicentre, national, randomised, double-blind, placebo-controlled intervention study. Participants will be recruited from four tertiary paediatric endocrine units in Denmark that manage boys with KS. Participants will be randomised to treatment with transdermal placebo or transdermal testosterone (Androgel; Besins Healthcare, Paris, France) with dose titration every 3 months based on individual measurements of serum concentrations of testosterone. Dose titration will be conducted by a single physician to ensure free testosterone remains between +1 and +3 SD for age.Thorough clinical and biochemical evaluation will be performed at baseline, after 12 months and 24 months. Additional visits for minor evaluations will occur every 3 months. Neuropsychological assessment will be conducted at baseline and after 24 months of treatment.Ethics and disseminationThe study will be conducted in accordance with the Helsinki Declaration. The study has been approved by the Danish National Medical Research Ethics Committee and the Danish Medicines Agency (Clinical trials information system number 2023-505854-16-00). Results will be submitted for publication in peer-reviewed journals.Trial registration numberNCT06294990.

Project description:Klinefelter syndrome (KS, 47,XXY) is the most common sex chromosome aneuploidy in males. A variety of complex clinical needs is associated with KS, including physical, cognitive and psychosocial impairments. Standard treatment for KS consists of androgen replacement therapy in adolescence to offset testosterone deficiency. Such treatment has a beneficial effect on the physical and behavioral manifestations of this syndrome. Whether androgen supplementation has a significant influence on the brain, however, is unknown. In the current study, we examined regional gray matter volume in boys with KS to assess whether treatment with oxandrolone, a synthetic hormone analog of testosterone, was associated with structural changes in the brain. Specifically, we focused our investigation on the hippocampus, given (1) its involvement in KS, and (2) the high concentration of androgen receptors found in this region. Structural magnetic resonance imaging data was acquired from a subsample of boys who completed a 2-year double-blind clinical trial in which patients were randomized to treatment with oxandrolone or to placebo, as well as from a sample of typically developing (TD) boys. Group differences in hippocampal volume were examined. A significant main effect of group was observed. Pairwise comparisons indicated smaller hippocampal volume in the placebo group relative to the oxandrolone group, as well as smaller volume in the placebo group relative to the TD control group. No difference in volume was observed between the treatment and TD groups. Moreover, across KS subgroups, a significant positive association was observed between hippocampus volume and performance on a spatial memory task, indicating treatment-based changes in brain structure may underlie cognitive change. These findings confirm prior reports implicating a role of the hippocampus in KS and are important in extending previous research by demonstrating a significant effect of androgens on brain structure.

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Morbidity in Klinefelter syndrome and the effect of testosterone treatment.

Publications

Morbidity in Klinefelter syndrome and the effect of testosterone treatment.

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