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

ABSTRACT 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.