Free testosterone and IGF-I mediate sex-specific linear growth during minipuberty.

Objective: Postnatal growth velocity peaks in early infancy with transient sex differences, and about 15% of adult height is gained in the first year. This period overlaps with minipuberty, the temporary activation of the hypothalamic-pituitary-gonadal axis. Although minipuberty is critical for reproductive development, its role in somatic growth and its interaction with IGF-I remain unclear. We investigated (i) the relationship between free testosterone (free T) and growth velocity in early infancy, (ii) sex differences in these associations, and (iii) whether IGF-I mediates these effects. Design: Prospective, longitudinal, population-based birth cohort study (Copenhagen Minipuberty Study, 2016-2018 (ClinicalTrials.gov identifier NCT02784184); one-year follow-up). Methods: A total of 189 healthy, full-term, appropriate-for-gestational-age infants (88 girls and 101 boys) were followed from birth with repeated anthropometric and hormonal assessments up to 12 months of age. Results: After birth, growth velocity declined in both sexes, with boys growing faster during the first three months before trajectories converged. Free T was positively associated with growth velocity, most strongly in boys. In boys, shifting free T from the 25th to 75th percentile corresponded to an 8.3 cm/year higher growth velocity (95% CI: 3.5-15.3), of which 32.6% (95% CI: 15.3-85.3) was mediated via IGF-I. In girls, indirect effects via IGF-I were modest (0.8 cm/year, 95% CI: 0.05-1.8), while direct effects were not significant. Conclusion: Free testosterone contributes to early postnatal growth both directly and indirectly via IGF-I, with stronger effects in boys. These findings underscore sex-specific endocrine regulation of infant growth and suggest that androgen activity during minipuberty may influence long-term growth trajectories. Significance statement: During the first months of life, boys grow faster than girls, but the hormonal mechanisms underlying this difference are not well understood. This study shows that free testosterone during minipuberty contributes to early linear growth, particularly in boys, and that part of this association is mediated through IGF-I. By combining longitudinal growth data with serum hormone measurements, our findings identify an early interaction between androgen activity and the IGF-I axis. These results extend established concepts of sex steroid-dependent growth to infancy and highlight minipuberty as an important period for somatic growth.