Shanlee M Davis, Susan Howell, Jennifer Janusz, Najiba Lahlou, Regina Reynolds, Talia Thompson, Karli Swenson, Rebecca Wilson, Judith L Ross, Philip S Zeitler, Nicole R Tartaglia
The Journal of Clinical Endocrinology & Metabolism, Volume 110, Issue 12, December 2025, Pages 3493–3504
https://doi.org/10.1210/clinem/dgaf217
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.
We tested the hypothesis that exogenous testosterone treatment positively affects short-term physical, hormonal, and neurodevelopmental outcomes in infants with XXY.
Double-blind randomized controlled trial, 2017-2021.
US tertiary care pediatric hospital.
Infants 30 to 90 days of age with prenatally identified, nonmosaic 47,XXY (n = 71).
Testosterone cypionate 25 mg IM injections every 4 weeks for 3 doses.
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.
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).
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.
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