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Schmidt et al. J Transl Genet Genom 2024;8:77-84 https://dx.doi.org/10.20517/jtgg.2023.43 Page 79

EHT consists of testosterone injections administered during minipuberty in infancy. In typically developing
boys, this minipuberty generally occurs between 1-6 months of age, and has an impact on brain
development, maturation of sexual organs, and the promotion of social behaviors [11-13] . One study by
[14]
Cabrol et al. included 38 infants with 47,XXY, and measured testosterone levels during minipuberty . They
found that testosterone concentrations were significantly lower in infants with 47,XXY compared to
controls. Therefore, administering EHT mimics the testosterone surge that occurs in typically developing
infants, and may mitigate the impact of androgen deficiency associated with 47,XXY.

The impact of HRT on the growth patterns of males with 47,XXY has been under-investigated and is not
well understood at this time. However, there are long-held beliefs that testosterone replacement in young
children may affect growth patterns or initiate puberty, though there are not any substantive studies in
research literature documenting these findings. These beliefs have impacted families seeking care from their
pediatric medical providers. Notably, there have not been any longitudinal comprehensive studies looking
at the effect of HRT on growth in individuals with 47,XXY between infancy and the preschool years.
Additionally, in these studies, cohorts have been small and there have been few natural history studies on
anthropometric parameters in males with 47,XXY. The present study aims to evaluate the effect of
testosterone on growth velocity and proportion in males with 47,XXY from birth to five years of age, as well
as to expand on the literature discussing their anthropometric patterns.

MATERIALS AND METHODS
134 boys aged from birth to 60 months were enrolled in this study. All participants had a prenatal diagnosis
of 47,XXY and had been referred by their primary care physician, parents, or other ancillary healthcare
providers for neurodevelopmental evaluation, including anthropometric measurements of height, weight,
and head circumference. Head circumference measurements were obtained by encircling the cranium with
a measuring tape, one centimeter above the eyes and against the occipital region of the head. Length and
weight were obtained in a supine position for those under 2 years of age. In children above three years,
height was measured using a sliding measurement tool in a standing position and weight was obtained by
standing on a standard upright scale. At the time of enrollment, prenatal, perinatal, and postnatal history, as
well as family demographics and a three-generation family history, were collected.

Each patient’s visit, including head circumference, height, and weight measurements at the time of the visit,
was treated as an individual data point. This would serve as the most accurate method of ascertaining the
association between growth velocity and testosterone administration. Patients under 2 years of age were
seen once every 6 months and patients between 2 years of age and 5 years were seen once every year. There
were 268 data points. 175 data points received testosterone injections as treatment, and 93 points did not
participate in EHT and instead served as the “no treatment” (No-T) group.

Patients were evaluated by pediatric endocrinologists throughout the United States and local to their
communities to determine the need for HRT. EHT was administered between the ages of 4- and 15-months.
EHT consisted of three intramuscular injections of 25 mg of testosterone enanthate given over three
[15]
months. Treatment was typically given at 4, 5, and 6 months of age but may be given up to 24 months .

The statistical analysis was completed in MATLAB R2019b using the statistics toolbox. A t-test was
completed for analysis to compare two groups of males, those who received EHT and those who did not
(T vs. No-T). P-values of < 0.05 were considered statistically significant.