Sex Steroids Balance for Metabolic and Reproductive Health in Klinefelter Syndrome

Study Overview
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Brief Summary
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The study seeks primarily to determine whether modulation of systemic and testicular sex steroids balance by aromatase inhibitors will positively affect the metabolic health and spermatogenesis of men with Klinefelter syndrome (KFS) as compared to the current state of the art for each issue. Secondary objectives of this study are (i) to unravel the heterogeneity of the reproductive and metabolic phenotype of men with KFS by performing a multi-omic analysis in a large cohort at baseline; (ii) to evaluate the efficacy of semaglutide-induced weight loss to achieve metabolic and reproductive benefit in men with Klinefelter syndrome as compared to standard testosterone replacement; (ii) to assess whether addition of hCG to aromatase inhibitors further increases intratesticular testosterone and promotes spermatogenesis in men with KFS.

Official Title
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Dissecting the Importance of Sex Steroids Balance for Metabolic and Reproductive Health in Men With Klinefelter Syndrome: a Randomized Controlled Study

Conditions
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Klinefelter Syndrome

Intervention / Treatment
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* Drug: Anastrozole
* Drug: Semaglutide
* Drug: human chorionic gonadotropin
* Drug: Testosterone gel


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: -Diagnosis of Klinefelter syndrome (47,XXY or mosaicism) Design 1: Age range: 16-40 years old Intention to become parent or interest in fertility preservation Confirmed azoospermia (lack of spermatozoids) after centrifugation of 2 semen samples Design 2: Age range: 18-65 years old No interest in fertility or fertility preservation Hypogonadism at diagnosis or after wash-out of testosterone replacement therapy High metabolic risk defined as severe overweight (BMI ≥ 28 kg/m2) or BMI 25-28 kg/m2 with insulin resistance (HOMA-IR > 2.6) Exclusion Criteria: Contraindications to testosterone-rising therapies (prostate or breast cancer, PSA > 4 µg/l, active liver disease, symptomatic heart disease) Decreased life expectancy due to terminal disease Known or suspected non-compliance, drug or alcohol abuse Inability to follow the procedures of the study (language problems, severe psychological or mental disorders)

Ages Eligible for Study
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Minimum Age: 16 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Two designs according to the presence of fertility desire (Design 1) or high metabolic risk (Design 2)
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Design 1 (Fertility) - positive micro-dissection testicular sperm extraction (mTESE) biopsy 1<br>Men with Klinefelter syndrome seeking fertility or interested in fertility preservation that undergo mTESE biopsy after wash-out of testosterone replacement therapy and have positive sperm retrieval (detectable spermatozoids) | |
| Experimental: Design 1 (Fertility) - negative mTESE biopsy 1, then randomized to Group A<br>Men with Klinefelter syndrome seeking fertility or interested in fertility preservation that undergo mTESE biopsy after wash-out of testosterone replacement therapy and have negative sperm retrieval (no detectable spermatozoids), subsequently randomized to receive an hormonal stimulation for 26 weeks | Drug: Anastrozole<br>* This will be an experimental treatment for 26 weeks in Design 1 Group A and Group B as well for Design 2 Group D<br>* Other names: Anastrozole Teva;|
| Experimental: Design 1 (Fertility) - negative mTESE biopsy 1, then randomized to Group B<br>Men with Klinefelter syndrome seeking fertility or interested in fertility preservation that undergo mTESE biopsy after wash-out of testosterone replacement therapy and have negative sperm retrieval (no detectable spermatozoids), subsequently randomized to receive an hormonal stimulation for 26 weeks | Drug: Anastrozole<br>* This will be an experimental treatment for 26 weeks in Design 1 Group A and Group B as well for Design 2 Group D<br>* Other names: Anastrozole Teva;Drug: human chorionic gonadotropin<br>* This will be an experimental treatment for 26 weeks in addition to anastrozole in Design 1 -Group B<br>* Other names: Choriomon;|
| Active Comparator: Design 2 (Metabolic Risk) - randomized to Group C<br>Men with Klinefelter syndrome not interested in fertility that present with high metabolic risk and consent to a wash-out of testosterone replacement therapy. They are subsequently randomized to receive an hormonal treatment to improve metabolic health. This arm will receive an active comparator by a testosterone gel | Drug: Testosterone gel<br>* This will be an active comparator for 26 weeks in Design 2 - Group C<br>* Other names: Tostran;|
| Experimental: Design 2 (Metabolic Risk) - randomized to Group D<br>Men with Klinefelter syndrome not interested in fertility that present with high metabolic risk and consent to a wash-out of testosterone replacement therapy. They are subsequently randomized to receive an hormonal treatment to improve metabolic health. This arm will receive an an experimental treatment | Drug: Anastrozole<br>* This will be an experimental treatment for 26 weeks in Design 1 Group A and Group B as well for Design 2 Group D<br>* Other names: Anastrozole Teva;|
| Experimental: Design 2 (Metabolic Risk) - randomized to Group E<br>Men with Klinefelter syndrome not interested in fertility that present with high metabolic risk and consent to a wash-out of testosterone replacement therapy. They are subsequently randomized to receive an hormonal treatment to improve metabolic health. This arm will receive an an experimental treatment | Drug: Semaglutide<br>* This will be an experimental treatment for 26 weeks in Design 2 Group E<br>* Other names: Ozempic;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Design 1 : sperm retrieval rate at mTESE biopsy | Sperm retrieval rate at mTESE biopsy (Group A and B) | mTESE biopsy 26 weeks after hormonal intervention | 
| Design 2 : change in insulin resistance index (HOMA-IR) | HOMA-IR calculated using fasting glucose and insulin levels | From baseline to week 26 of intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Metabolic syndrome, Infertility, Aromatase, Testosterone/estradiol ratio, mTESE biopsy, GLP1 agonists