Testosterone Effects on Short-Term Physical, Hormonal, and Neurodevelopmental Outcomes in Infants with 47,XXY/Klinefelter Syndrome: The TESTO Randomized Controlled Trial
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Updated: Jun 4, 2025
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Published on: March 2, 2011
Shanlee Davis1,2, Susan Howell2, Jennifer Janusz3
1Department of Pediatrics, Section of Endocrinology, University of Colorado SOM, Aurora, Colorado, USA.
Insights
Testosterone treatment in infants with Klinefelter syndrome (XXY) improved body composition but did not affect neurodevelopment. The treatment suppressed the hormonal axis, suggesting it is not routinely recommended for infants with XXY.
Area of Science:
- Pediatric Endocrinology
- Developmental Biology
- Genetics
Background:
- Klinefelter syndrome (47,XXY) is linked to impaired testicular function, growth, metabolism, and neurodevelopmental differences.
- These clinical features may stem from insufficient testosterone during infancy's mini-puberty phase.
Purpose of the Study:
- To investigate the effects of exogenous testosterone on short-term physical, hormonal, and neurodevelopmental outcomes in infants with 47,XXY.
- To test the hypothesis that testosterone treatment positively influences these outcomes.
Main Methods:
- A double-blind randomized controlled trial was conducted between 2017 and 2021.
- Participants included 71 infants (30-90 days old) with prenatally identified, non-mosaic 47,XXY.
- Intervention involved intramuscular testosterone cypionate injections (25mg) every 4 weeks for 3 doses.
Main Results:
- Testosterone treatment led to a significant increase in lean mass and a decrease in fat mass z-scores at 12 weeks.
- Testosterone administration suppressed gonadotropins and inhibin B levels.
- No significant differences were observed in short-term motor, cognitive, or language outcomes between groups.
Conclusions:
- Testosterone injections in infants with 47,XXY show physical effects related to androgen exposure but do not impact neurodevelopment.
- The treatment suppressed the hypothalamic-pituitary-gonadal axis.
- Current findings do not support routine testosterone use in infants with 47,XXY, though long-term follow-up is necessary.
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.
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