Testosterone Effects on Short-term Physical, Hormonal, and Neurodevelopmental Outcomes (TESTO) in Infants With 47,XXY.

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 influenced by testosterone during the minipuberty period of infancy.

OBJECTIVE

We tested the hypothesis that exogenous testosterone treatment positively affects 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 to 90 days of age with prenatally identified, nonmosaic 47,XXY (n = 71).

INTERVENTION: Testosterone cypionate 25 mg IM injections every 4 weeks for 3 doses.

MAIN OUTCOME MEASURES: The a priori primary outcomes were change in percent fat mass z-scores and change in the total composite percentile on Alberta Infant Motor Scales assessment from baseline to 12 weeks.

RESULTS

The between-group difference in change in percent fat mass z-scores was -0.57 (95% CI, -1.1 to -0.06; P = .03), secondary to greater increases in lean mass in the testosterone-treated group (1.5 ± 0.4 kg vs 1.2 ± 0.4; P = .001). Testosterone suppressed gonadotropins and inhibin B (P < .001 for all). In contrast, there were no significant group differences in short-term motor, cognitive, or language outcomes (P > .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, this dose suppressed the hypothalamic-pituitary-gonadal axis. Neurodevelopment outcomes were not impacted by treatment. 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.