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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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Testosterone | Active Comparator | Testosterone gel applied to the skin |
|
| Placebo | Placebo Comparator | Placebo gel applied to the skin |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Testosterone gel | Drug | Two years treatment with testosterone |
|
| Measure | Description | Time Frame |
|---|---|---|
| Changes in body fat mass | Evaluation of body fat percentage by whole body dual energy x-ray absorptiometry (DEXA) scan | Baseline and 1 and two years |
| Measure | Description | Time Frame |
|---|---|---|
| Pubertal development and virilization | Tanner genital (G) staging from G1 to G5. G1 is the prepubertal stage and G5 is the fully develloped stage. | Every three months for two years |
| Pubertal development and virilization |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Lise Aksglaede, MD | Contact | +45 35455064 | lise.aksglaede@regionh.dk |
| Name | Affiliation | Role |
|---|---|---|
| Lise Aksglaede, MD | Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Copenhagen University Hospital, Rigshospitalet | Recruiting | Copenhagen | 2100 | Denmark |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 40090688 | Derived | Caspersen ID, Fritzboger AFO, Petersen JH, Birkebaek N, Christensen AR, Schou AJ, Kristensen K, Ross JL, Davis S, Butler G, van Rijn S, Juul A, Aksglaede L. Effect of testosterone treatment during puberty in boys with Klinefelter syndrome (The TIPY Study): protocol for a nationwide randomised, double-blinded, placebo-controlled study. BMJ Open. 2025 Mar 15;15(3):e095628. doi: 10.1136/bmjopen-2024-095628. |
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| ID | Term |
|---|---|
| D007713 | Klinefelter Syndrome |
| ID | Term |
|---|---|
| D058533 | Sex Chromosome Disorders of Sex Development |
| D012734 | Disorders of Sex Development |
| D014564 | Urogenital Abnormalities |
| D052776 | Female Urogenital Diseases |
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| ID | Term |
|---|---|
| D013739 | Testosterone |
| ID | Term |
|---|---|
| D000737 | Androstenols |
| D000736 | Androstenes |
| D000731 | Androstanes |
| D013256 | Steroids |
| D000072473 |
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Multi-center, national, randomized, double-blind, placebo-controlled intervention study
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| Placebo | Other | Two years treatment with placebo |
|
|
Tanner pubic hair (PH) staging from PH1 to PH6. PH1 is the prepubertal stage and PH6 is the fully develloped stage.
| Every three months for two years |
| Pubertal development and virilization | Measurement of voice frequency using the app "Voice Analyst" (Speechtools Ltd.). | Every three months for two years |
| Pubertal development and virilization | Evaluation of testicular volume by palpation with orchidometer | Every three months for two years |
| Pubertal development and virilization | Presence of gynecomastia (yes/no) | Every three months for two years |
| Pubertal development and viriliztion | Measurement of luteinizing hormone (LH) (IU/L) in serum | Every three months for two years |
| Pubertal development and viriliztion | Measurement of serum concentration of testosterone (nmol/L) | Every three months for two years |
| Pubertal development and viriliztion | Measurement of folliclestimulating hormone (FSH) (IU/L) in serum | Every three months for two years |
| Pubertal development and viriliztion | Measurement of serum concentration of estradiol (pmol/L) | Every three months for two years |
| Pubertal development and viriliztion | Measurement of serum concentration of inhibin B (ng/L) | Every three months for two years |
| Pubertal development and viriliztion | Measurement of serum concentration of anti mullerian hormone (AMH) (pmol/L) | 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. | At base line, and at 1 and 2 years |
| Anthropometry | Measurement of height (cm) | Every three months for two years |
| Anthropometry | Measurement of weight (kg) | Every three months for two years |
| Anthropometry | Measurement of sitting height (cm) | Every three months for two years |
| Anthropometry | Measurement of head circumference (cm) | At base line, and at 1 and 2 years |
| Anthropometry | Measurement of arm span (cm) | 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 | 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) | At base line, and at 1 and 2 years |
| Measurement of bone turnover markers | Measurement of 25-OH-vitamin D in blood sample | At base line, and at 1 and 2 years |
| Measurement of bone turnover markers | Measurement of calcium in blood sample | At base line, and at 1 and 2 years |
| Measurement of bone turnover markers | Measurement of phosphate in blood sample | At base line, and at 1 and 2 years |
| Measurement of bone turnover markers | Measurement of parathyroid hormone (PTH) in blood sample | 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 | At base line, and at 1 and 2 years |
| Measurement of bone turnover markers | Measurement of alkaline phosphatase in blood sample | At base line, and at 1 and 2 years |
| Measurement of bone turnover markers | Measurement of osteocalcin in blood sample | 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 | 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) | 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) | At base line, and at 1 and 2 years |
| Muscle strength | Measurement of standing jump length (cm) | 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) | Every three months for two years |
| Changes i QTc | Evaluation of QT Interval with electrocardiogram (ECG) | Base line and at 1 and 2 years |
| Changes in markers of lipids | Measurement of cholesterol in blood sample | Base line and at 1 and 2 years |
| Changes in markers of metabolism | Measurement of adiponectin in blood sample | Base line and at 1 and 2 years |
| Changes in markers of metabolism | Measurement of leptin in blood sample | Base line and at 1 and 2 years |
| Changes in markers of metabolism | Measurement of glucose in blood sample | Base line and at 1 and 2 years |
| Changes in markers of metabolism | Measurement of insulin in blood sample | Base line and at 1 and 2 years |
| Changes in markers of metabolism | Measurement of HbA1C in blood sample | Base line and at 1 and 2 years |
| Changes in markers of inflammation | Measurement of CRP in blood sample | 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. | 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. | 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. | 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. | Baseline and after two years |
| Neuropsychological evaluation | The Mental Rotation Test | Baseline and after two years |
| Neuropsychological evaluation | The Beery-Buktenica Developmental Test of Visual-Motor Integration | Baseline and after two years |
| Neuropsychological evaluation | The Baseline Speed subtask of the Amsterdam Neuropsychological Tasks program (ANT) | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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. | 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 | 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. | 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. | 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. | At base line, and at 1 and 2 years |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D052801 | Male Urogenital Diseases |
| D025064 | Sex Chromosome Disorders |
| D025063 | Chromosome Disorders |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D030342 | Genetic Diseases, Inborn |
| D006058 | Gonadal Disorders |
| D004700 | Endocrine System Diseases |
| D007006 | Hypogonadism |
| Fused-Ring Compounds |
| D011083 | Polycyclic Compounds |
| D045165 | Testosterone Congeners |
| D012739 | Gonadal Steroid Hormones |
| D042341 | Gonadal Hormones |
| D006728 | Hormones |
| D006730 | Hormones, Hormone Substitutes, and Hormone Antagonists |