Klinefelter Syndrome and Testosterone Treatment in Puberty
- Registration Number
- NCT06294990
- Lead Sponsor
- Lise Aksglæde
- Brief Summary
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.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- RECRUITING
- Sex
- Male
- Target Recruitment
- 32
- 47,XXY Klinefelter syndrome
- Age 10-14 years at inclusion
- Luteinizing Hormone > +2 standard deviations (SD) by ultrasensitive luteinizing hormone assay
- Free Testosterone<+2 standard deviations
- Signed consent from parents
- Previous or ongoing T treatment except for TRT because of micropenis
- Contraindications to testosterone treatment known hypersensitivity to testosterone or to any other constituent of the gel known or suspected prostatic cancer or breast carcinoma
- Participation in any other clinical trial
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Placebo Placebo Placebo gel applied to the skin Testosterone Testosterone gel Testosterone gel applied to the skin
- Primary Outcome Measures
Name Time Method Changes in body fat mass Baseline and 1 and two years Evaluation of body fat percentage by whole body dual energy x-ray absorptiometry (DEXA) scan
- Secondary Outcome Measures
Name Time Method Pubertal development and virilization Every three months for two years Presence of gynecomastia (yes/no)
Pubertal development and viriliztion Every three months for two years Measurement of serum concentration of anti mullerian hormone (AMH) (pmol/L)
Pubertal development At base line, and at 1 and 2 years Measurement of the concentration of luteinizing hormone (LH) and follicle stimulating hormone (FSH) in the first, fasting, morning voiding. Measured in IU/L.
Anthropometry At base line, and at 1 and 2 years Measurement of arm span (cm)
Bone health At base line, and at 1 and 2 years Evaluation of bone health index (BHI) from X-ray of left hand and evaluated using the software BoneXpert version 3 (Hørsholm, Denmark)
Measurement of bone turnover markers At base line, and at 1 and 2 years Measurement of procollagen type I N-terminal peptide (PINP) in blood sample
Changes in growth Base line and at 1 and 2 years Evaluation of bone age by X-ray of left hand and evaluated using the software BoneXpert version 3 (Hørsholm, Denmark)
Measurement of serum concentrations of growth factors At base line, and at 1 and 2 years Measurement of IGF1, IGF2, IGF1BP-1-6 and acid-labile subunit (ALS)) (microg/L)
Muscle strength Every three months for two years Measurement of hand grip strength using a digital hand dynamometer (Baseline BIMS, digital hand dynamometer, functional model)
Changes i QTc Base line and at 1 and 2 years Evaluation of QT Interval with electrocardiogram (ECG)
Changes in markers of lipids Base line and at 1 and 2 years Measurement of cholesterol in blood sample
Changes in markers of metabolism Base line and at 1 and 2 years Measurement of HbA1C in blood sample
Changes in markers of inflammation Base line and at 1 and 2 years Measurement of CRP in blood sample
Neuropsychological evaluation Baseline and after two years 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.
Cryopreservation of spermatozoa After 2 years If the patient is able and willing he will have the possibility to deliver a semen sample for cryopreservation of potential spermatozoa
Epigenetic At base line, and at 1 and 2 years 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.
Genetic effects At base line, and at 1 and 2 years 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.
Small non-coding RNA At base line, and at 1 and 2 years RNA analysis of circulating, small, non-coding RNA will be performed as a biomarker for the circulating concentrations of reproductive hormones and for overweight.
Trial Locations
- Locations (1)
Copenhagen University Hospital, Rigshospitalet
🇩🇰Copenhagen, Denmark