Does height and IGF-I determine pubertal timing in girls?

BACKGROUND: Pubertal timing is closely linked to growth regulated by the growth hormone/insulin-like factor (GH/IGF) axis that includes IGF-regulating factors such as pregnancy-associated plasma protein-A/A2 (PAPP-A/PAPP-A2) and stanniocalcin 2 (STC2). We investigated the association between height, IGF-I concentration, and PAPPA, PAPPA2, and STC2 genotypes on the timing of female pubertal milestones. METHODS: Height, IGF-I, and genotypes were analyzed in 1382 Danish girls from the general population, 67 patients with tall stature (height ≥2 SD), and 124 patients with short stature (height ≤-2 SD). The main outcomes were breast stage and menarche. RESULTS: Thelarche occurred significantly earlier in patients with tall stature (mean age 9.37 years [95% confidence interval (CI) 8.87-9.87]) and later in patients with short stature (11.07 years [95% CI 10.7-11.43]) compared with girls within the normal range (9.96 years [95% CI 9.85-10.07]) (p = 0.02 and p < 0.01, respectively). Girls with higher IGF-I levels experienced thelarche and menarche earlier compared with the rest of the cohort (p < 0.01). Genotypes were not associated with age at thelarche nor menarche, but the PAPPA2 minor allele carriers were shorter compared with major allele carriers, p = 0.03. CONCLUSIONS: Height and IGF-I, but not PAPP-A, PAPP-A2, and STC2 genotypes, were negatively associated with age at thelarche and menarche. IMPACT: Girls with tall and short stature enter puberty earlier and later compared with girls with normal height. Girls with higher insulin-growth factor-I in childhood enter puberty earlier. Pubertal timing is influenced by longitudinal growth and IGF-I levels earlier in childhood. Childhood growth and the levels of IGF-I in childhood may be biomarkers of pubertal timing.