Testosterone Not Backed for Universal Use in Infants with Klinefelter Syndrome

Research study background

As cell-free DNA screening during pregnancy becomes standard, clinicians are increasingly identifying sex chromosome aneuploidies (variations) in infants. Klinefelter syndrome (47, XXY), the most common variation, affects approximately 1 in 600 males. Hallmarks of XXY include impaired testicular function, infertility and differences in physical growth, metabolism and neurodevelopment, leading to increased morbidity and mortality.

In the first months of life, males undergo a surge in testosterone production, which is believed to influence body composition, reproduction and potentially neurocognition. Clinical features of XXY may be attributed to inadequate testosterone during this “mini-puberty” period of infancy.

A 2019 pilot study from researchers at Children’s Hospital Colorado found that testosterone treatment in infants with XXY improved body composition compared to untreated peers. These findings, along with other emerging evidence, have increased interest in early detection and intervention to optimize developmental outcomes — potentially even before clinical symptoms emerge. Building on their pilot, the current research hypothesized that testosterone injections during the mini puberty period would offer short-term physical, hormonal and neurodevelopmental benefits to infants with XXY.

This double-blind prospective clinical trial tested the efficacy and safety of testosterone treatment in 72 infants with non-mosaic XXY who were 31 to 90 days old. Participants were randomized to receive testosterone cypionate or placebo injections for three months, followed by a three-month crossover to the alternate treatment. After each 12-week period, researchers assessed baseline measures of growth (length and weight), body composition (fat and lean mass) and circulating hormone levels and conducted thorough neurodevelopmental assessments.

Relevance to practice

This study was the first randomized trial of its kind. Infants who received testosterone, compared to those who received the placebo, experienced accelerated linear growth and increased lean mass, which aligns with findings from the pilot study. The results also revealed that testosterone injections suppressed natural hormone levels. This may indicate possible negative effects on the hypothalamic-pituitary-gonadal axis and calls into question assumptions that short-term testosterone treatment is harmless.

While testosterone treatment in infants with XXY impacted physical outcomes and were overall well-tolerated, there were no short-term neurological benefits. Study authors reported no statistically significant differences in motor skills, language acquisition, cognitive abilities or behavioral patterns between the two groups. This diverges from literature associating testosterone treatment in infants with neurodevelopmental benefits.

The results do not support universal adoption of testosterone treatment into current clinical practice for infants with XXY. Instead, clinicians should closely monitor and assess these patients for early intervention needs from birth until age 5.

Researchers concluded that further investigation and ongoing follow up is needed to determine any long-term consequences of hormone alteration, the sustainability of body composition benefits and potential emergence of neurodevelopmental benefits in treated infants.