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.

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 one semen sample

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 overweight (BMI 25-28 kg/m2) and 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)

Upon reasonable request and data transfer agreement

At study completion