The goal of this randomized clinical trial is to study the effect of testosterone replacement therapy during puberty in boys with Klinefelter syndrome (KS, 47,XXY). The main questions to answer are how treatment with testosterone will affect body fat mass, lipid and glucose metabolism, growth and body proportions, bone mineralization as well as effects on neurocognitive development and emotional and social difficulties. Participants will be randomized to two years treatment with testosterone or placebo.
Klinefelter syndrome (KS, 47,XXY) is the most frequent sex chromosome disorder with a prevalence of 1:660 boys. Patients with KS are hypogonadal due to a progressive testicular destruction starting already in childhood. Consequently, the adult male with KS is characterized by small testes, signs of incomplete virilization (e.g. lack of voice deepening, sparse face and body hair, gynecomastia, low muscle mass, reduced penile length), hypergonadotropic hypogonadism, infertility and increased risk of metabolic syndrome, diabetes, cardiovascular disease, osteoporosis and psychosocial and neurodevelopmental challenges. Adults with KS have a poor health and a prevention of the major co-morbidities associated with KS and thereby an improvement in the general health would have an enormous impact on the life of a large cohort of males worldwide. Sufficient testosterone is not only important in the adult but also during puberty and adolescence for a normal virilization and to improve body composition and body proportions, as well as to maximize peak bone mass acquisition. It has therefore been internationally accepted and makes biological sense to consider testosterone replacement therapy (TRT) during puberty in KS. However, there are no evidence based recommendations, and during recent years TRT in puberty has been questioned and is no longer recommended in some countries. There is a need on an international level for evaluating the effect of this treatment. We therefore aim at evaluating the effect of 2 years TRT during early puberty in boys with KS aged 10 to 14 years in this national, multi-center, randomized, double-blind, placebo-controlled intervention study. The primary endpoint is to evaluate the effect on body fat mass. The secondary endpoints are to evaluate effects on lipid and glucose metabolism, growth and body proportions, bone mineralization as well as effects on neurocognitive development and emotional and social difficulties.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Two years treatment with testosterone
Two years treatment with placebo
Copenhagen University Hospital, Rigshospitalet
Copenhagen, Denmark
RECRUITINGChanges in body fat mass
Evaluation of body fat percentage by whole body dual energy x-ray absorptiometry (DEXA) scan
Time frame: Baseline and 1 and two years
Pubertal development and virilization
Tanner genital (G) staging from G1 to G5. G1 is the prepubertal stage and G5 is the fully develloped stage.
Time frame: Every three months for two years
Pubertal development and virilization
Tanner pubic hair (PH) staging from PH1 to PH6. PH1 is the prepubertal stage and PH6 is the fully develloped stage.
Time frame: Every three months for two years
Pubertal development and virilization
Measurement of voice frequency using the app "Voice Analyst" (Speechtools Ltd.).
Time frame: Every three months for two years
Pubertal development and virilization
Evaluation of testicular volume by palpation with orchidometer
Time frame: Every three months for two years
Pubertal development and virilization
Presence of gynecomastia (yes/no)
Time frame: Every three months for two years
Pubertal development and viriliztion
Measurement of luteinizing hormone (LH) (IU/L) in serum
Time frame: Every three months for two years
Pubertal development and viriliztion
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Purpose
TREATMENT
Masking
TRIPLE
Enrollment
32
Measurement of serum concentration of testosterone (nmol/L)
Time frame: Every three months for two years
Pubertal development and viriliztion
Measurement of folliclestimulating hormone (FSH) (IU/L) in serum
Time frame: Every three months for two years
Pubertal development and viriliztion
Measurement of serum concentration of estradiol (pmol/L)
Time frame: Every three months for two years
Pubertal development and viriliztion
Measurement of serum concentration of inhibin B (ng/L)
Time frame: Every three months for two years
Pubertal development and viriliztion
Measurement of serum concentration of anti mullerian hormone (AMH) (pmol/L)
Time frame: Every three months for two years
Pubertal development
Measurement of the concentration of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in the first, fasting, morning voiding. Measured in IU/L.
Time frame: At base line, and at 1 and 2 years
Anthropometry
Measurement of height (cm)
Time frame: Every three months for two years
Anthropometry
Measurement of weight (kg)
Time frame: Every three months for two years
Anthropometry
Measurement of sitting height (cm)
Time frame: Every three months for two years
Anthropometry
Measurement of head circumference (cm)
Time frame: At base line, and at 1 and 2 years
Anthropometry
Measurement of arm span (cm)
Time frame: At base line, and at 1 and 2 years
Bone health
Measurement of whole body bone mineral content (BMC) evaluated by whole body DXA scan
Time frame: At baseline and at 1 and two years
Bone health
Evaluation of bone health index (BHI) from X-ray of left hand and evaluated using the software BoneXpert version 3 (Hørsholm, Denmark)
Time frame: At base line, and at 1 and 2 years
Measurement of bone turnover markers
Measurement of 25-OH-vitamin D in blood sample
Time frame: At base line, and at 1 and 2 years
Measurement of bone turnover markers
Measurement of calcium in blood sample
Time frame: At base line, and at 1 and 2 years
Measurement of bone turnover markers
Measurement of phosphate in blood sample
Time frame: At base line, and at 1 and 2 years
Measurement of bone turnover markers
Measurement of parathyroid hormone (PTH) in blood sample
Time frame: At base line, and at 1 and 2 years
Measurement of bone turnover markers
Measurement of carboxy terminal telopeptide of collagen type I (CTX) in blood sample
Time frame: At base line, and at 1 and 2 years
Measurement of bone turnover markers
Measurement of alkaline phosphatase in blood sample
Time frame: At base line, and at 1 and 2 years
Measurement of bone turnover markers
Measurement of osteocalcin in blood sample
Time frame: At base line, and at 1 and 2 years
Measurement of bone turnover markers
Measurement of procollagen type I N-terminal peptide (PINP) in blood sample
Time frame: At base line, and at 1 and 2 years
Changes in growth
Evaluation of bone age by X-ray of left hand and evaluated using the software BoneXpert version 3 (Hørsholm, Denmark)
Time frame: Base line and at 1 and 2 years
Measurement of serum concentrations of growth factors
Measurement of IGF1, IGF2, IGF1BP-1-6 and acid-labile subunit (ALS)) (microg/L)
Time frame: At base line, and at 1 and 2 years
Muscle strength
Measurement of standing jump length (cm)
Time frame: Every three months for two years
Muscle strength
Measurement of hand grip strength using a digital hand dynamometer (Baseline BIMS, digital hand dynamometer, functional model)
Time frame: Every three months for two years
Changes i QTc
Evaluation of QT Interval with electrocardiogram (ECG)
Time frame: Base line and at 1 and 2 years
Changes in markers of lipids
Measurement of cholesterol in blood sample
Time frame: Base line and at 1 and 2 years
Changes in markers of metabolism
Measurement of adiponectin in blood sample
Time frame: Base line and at 1 and 2 years
Changes in markers of metabolism
Measurement of leptin in blood sample
Time frame: Base line and at 1 and 2 years
Changes in markers of metabolism
Measurement of glucose in blood sample
Time frame: Base line and at 1 and 2 years
Changes in markers of metabolism
Measurement of insulin in blood sample
Time frame: Base line and at 1 and 2 years
Changes in markers of metabolism
Measurement of HbA1C in blood sample
Time frame: Base line and at 1 and 2 years
Changes in markers of inflammation
Measurement of CRP in blood sample
Time frame: Base line and at 1 and 2 years
Neuropsychological evaluation
The Weschler Intelligence Scale for Children - Fifth Edition (WISC-V). The result is based on a combination of seperate index scores. A higher score generally indicates stronger cognitive abilities.
Time frame: Baseline and after two years
Neuropsychological evaluation
The Test of Variables of Attention, version 9 (T.O.V.A) is a computerized, performance-based assessment tool used to measure attention and impulsivity. The result is based on a combination of scores.
Time frame: Baseline and after two years
Neuropsychological evaluation
The Test of Memory and Learning, Second Edition (Tomal-2). The results are presented as standard scores, scaled scores, percentile ranks, and index scores. A higher score is a better outcome.
Time frame: Baseline and after two years
Neuropsychological evaluation
The Judgement of Line Orientation Test. The result is based on a combination of scores. Higher scores indicate better visual-spatial judgment.
Time frame: Baseline and after two years
Neuropsychological evaluation
The Mental Rotation Test
Time frame: Baseline and after two years
Neuropsychological evaluation
The Beery-Buktenica Developmental Test of Visual-Motor Integration
Time frame: Baseline and after two years
Neuropsychological evaluation
The Baseline Speed subtask of the Amsterdam Neuropsychological Tasks program (ANT)
Time frame: Baseline and after two years
Neuropsychological evaluation
The Children's Communication Checklist (CCC-2). The result is evaluated based on 10 subscores. Higher scores indicate stronger communication skills.
Time frame: Baseline and after two years
Neuropsychological evaluation
The Social Responsiveness Scale-2 (SRS-2) is a standardized questionnaire used to assess social behavior and autism-related traits. Higher scores indicate greater social difficulties, while lower scores suggest stronger social skills.
Time frame: Baseline and after two years
Neuropsychological evaluation
The Delis-Kaplan Executive Function System (D-KEFS). Higher scores indicate better executive functioning, while lower scores may suggest difficulties with problem-solving, impulse control, or flexibility.
Time frame: Baseline and after two years
Neuropsychological evaluation
The Behavior Rating Inventory of Executive Function, Second Edition rating scale , parent version (BRIEF-2) assesses executive functioning. The result is based on a combination of scores. Higher scores indicate greater executive function difficulties.
Time frame: Baseline and after two years
Neuropsychological evaluation
Behavior Assessment System for Children, Third Edition (BASC-3), parent and self-report version. The result is based on a combination of scores. A higher score indicates more difficulties.
Time frame: Baseline and after two years
Neuropsychological evaluation
Self-report version of The Multidimensional Anxiety Scale for Children - 2nd edition (MASC-2). The result is based on a combination of scores. Higher scores suggest greater levels of anxiety and more severe symptoms.
Time frame: Baseline and after two years
Neuropsychological evaluation
The parent version of the ADHD-rating scale. The result is based on a combination of scores. Higher scores on the inattention and hyperactivity/impulsivity subscales suggest more significant ADHD symptoms.
Time frame: Baseline and after two years
Neuropsychological evaluation
The Adaptive Behavior Assessment System, Third Edition (ABAS-III) is a comprehensive tool used to assess adaptive functioning. The result is based on a combination of scores. A higher score indicates better adaptive functioning.
Time frame: Baseline and after two years
Neuropsychological evaluation
The Beck Youth Self-Concept Inventory is a tool designed to assess self-concept and self-esteem in children and adolescents. A high percentile rank (above 70) indicates a strong self-concept, while a low percentile rank (below 30) suggests low self-esteem or dissatisfaction.
Time frame: Baseline and after two years
Neuropsychological evaluation
PedsQL Multidimentional Fatigue Scale, parent, and self-report versions is a tool designed to assess fatigue levels in children and adolescents. The result is based on a combination of scores. A higher score indicates less fatigue (better energy levels and functioning). A lower score indicates more fatigue, suggesting that fatigue is significantly affecting the child's daily activities.
Time frame: Baseline and after two years
Cryopreservation of spermatozoa
If the patient is able and willing he will have the possibility to deliver a semen sample for cryopreservation of potential spermatozoa
Time frame: After 2 years
Epigenetic
The effects on epigenetics will be evaluation by evaluating changes in DNA methylation patterns. This will be analyzed on DNA from white blood cells by applying Illumina methylation arrays.
Time frame: At base line, and at 1 and 2 years
Genetic effects
DNA will be analyzed using a selected set of genetic polymorphisms in target genes with established or theoretic effects on hormone production and hormone receptor sensitivity. They will be analysed either by PCR genotyping or targeted sequencing (max. 200 selected genes). SNP arrays that exclusively target common variants, and not any rare variants, will be used to determine the influence of common genetic variation on the observed associations.
Time frame: At base line, and at 1 and 2 years
Small non-coding RNA
RNA analysis of circulating, small, non-coding RNA will be performed as a biomarker for the circulating concentrations of reproductive hormones and for overweight.
Time frame: At base line, and at 1 and 2 years