Testosterone Effects on Short-Term Physical, Hormonal, and Neurodevelopmental Outcomes in Infants with 47,XXY/Klinefelter Syndrome: The TESTO Randomized Controlled Trial.

Context: 47,XXY/Klinefelter syndrome (XXY) is associated with impaired testicular function and differences in physical growth, metabolism, and neurodevelopment. Clinical features of XXY may be attributable to inadequate testosterone during the mini-puberty period of infancy.

Objective: We tested the hypothesis that exogenous testosterone treatment positively effects short-term physical, hormonal, and neurodevelopmental outcomes in infants with XXY.

Design: Double-blind randomized controlled trial, 2017-2021.

Setting: US tertiary care pediatric hospital.

Patients: Infants 30-90 days of age with prenatally identified, non-mosaic 47,XXY (n=71).

Intervention: Testosterone cypionate 25mg intramuscular injections every 4 weeks for 3 doses.

Main outcome measures: The a priori primary outcomes were change in percent fat mass (%FM) z-scores and change in the total composite percentile on Alberta Infant Motor Scales (AIMS) assessment from baseline to 12 weeks.

Results: The between group difference in change in %FM z-scores was -0.57 [95% CI -1.1, -0.06], p=0.03), secondary to greater increases in lean mass in the testosterone-treated group (1.5±0.4 kg vs 1.2±0.4, p=0.001). Testosterone suppressed gonadotropins and inhibin B (p<0.001 for all). In contrast, there were no significant group differences in short term motor, cognitive, or language outcomes (p>0.15 for all).

Conclusions: In this double-blind randomized controlled trial in infants with XXY, testosterone injections resulted in physical effects attributable to systemic androgen exposure; however, there was no impact on neurodevelopmental outcomes and the hypothalamic-pituitary-gonadal axis was suppressed. These results do not support routine testosterone treatment in infants with XXY, however long term follow up on physical health, neurodevelopment and testicular function is needed.