ESPE Yearbook of Paediatric Endocrinology

J Clin Endocrinol Metab 2025. Online ahead of print.doi: 10.1210/clinem/dgaf217

Brief Summary: This randomized, double-blind, placebo controlled cross-over trial from one tertiary care center aimed to assess the safety and efficacy of monthly testosterone in prenatally identified, non-mosaic infants with 47,XXY. Infants with Klinefelter Syndrome undergo a mini-puberty, although measured blood testosterone concentrations are lower than average but usually within the low normal range. How this impacts on their many phenotypic features is unknown; some studies suggest that lower birth weight, mild hypotonia and a passive temperament may be subtle signs. Less than 10% of these infants have micropenis and/or cryptorchidism but most series document smaller penile and testicular size in infancy, but with gonadarche occurring at the expected age range¹. Non-randomized trials of early testosterone therapy described higher motor, cognitive, language and social skills, but well designed and powered trials have been lacking.

In this study, infants (n=71) aged between 30-90 days were randomized and were given either (group A) 25 mg i.m. testosterone cypionate every 28 d for 3 doses followed by 3 doses of saline i.m. saline, or (group B) 3 doses of saline followed by 3 doses of testosterone. Primary outcomes were the change in percent fat mass SDS from baseline to 12 weeks and the change in the total Alberta Infant Motor Scale (AIMS) during this same period. Secondary and exploratory outcomes included a change in scores from baseline to 12 weeks and 12-24 weeks for other body composition variables, anthropometric measurements, standard scores on a range of other development assessment tools, serum hormone concentrations, and adverse events. Unfortunately, COVID 19 prevented full completion of all the variables in a small group of patients in this study, although only 1 patient was lost to follow-up.

Results attributable to testosterone treatment included lower %FM SDS -0.57 [p=0.03] and greater increases in lean mass of1.5 kg vs 1.2 [p=0.001]. Penile length also increased, as did body length and weight. Expected side effects of testosterone therapy were noted (increased erection frequency, pubic hair, acne) but the treatment was well tolerated with no serious adverse events. As expected, blood concentrations of LH, FSH, and inhibin B were suppressed on treatment. There were no significant differences in all the observed short term motor, cognitive or language scores. The investigators concluded that routine testosterone treatment in infants with 47,XXY is not supported based on their neurodevelopmental data, but it will be important to continue with longer term follow up particularly on neurodevelopment, behavior and testicular function.

Reference: 1. AksglaedeL et al, Minipuberty in Klinefelter syndrome: Current status and future directions.Am J Med Genet C Semin Med Genet. 2020; 184(2): 320–326. doi: 10.1002/ajmg.c.31794.