Abstract
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
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Girls with tall and short stature enter puberty earlier and later compared with girls with normal height.
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Girls with higher insulin-growth factor-I in childhood enter puberty earlier.
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Pubertal timing is influenced by longitudinal growth and IGF-I levels earlier in childhood.
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Childhood growth and the levels of IGF-I in childhood may be biomarkers of pubertal timing.
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Acknowledgements
We thank the participating children and their families. We also thank the personnel in the molecular laboratory. This work was supported by the Candys Foundation (grant no. 2017-224). A.J. received funding from The Danish Research Council and The Capital Region of Denmark Research Fund for Health Research.
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E.N.U. contributed substantially to the conception and design, acquisition of data, or analysis and interpretation of data, drafted the initial paper, tables, and figures, and approved the final manuscript as submitted. A.S.B., K.A., and J.H.P. contributed substantially to the analysis and interpretation of data, revised the paper critically for important intellectual content, and approved the final version as submitted. K.M.M. and M.A. contributed substantially to the acquisition of data, revised the paper critically for important intellectual content, and approved the final version as submitted. A.J. and R.B.J. contributed substantially to the conception and design, acquisition of data or analysis, and interpretation of data, drafted the initial paper, and approved the final manuscript as submitted.
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A.J. has received an unrestricted research grant from Novo Nordisk (North European Study on GH treatment in short SGA children) and lecture fees from Novo Nordisk, Ferring, Ipsen, Sandoz, and Pfizer International. K.M.M. and R.B.J. have received lecture fees from Novo Nordisk. The other authors have nothing to declare.
Informed consent
Informed consent was obtained from all girls or their parents who participated in the population-based studies. Use of data from patients with short or tall stature was approved by the Danish Patient Safety Authority.
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Upners, E.N., Busch, A.S., Almstrup, K. et al. Does height and IGF-I determine pubertal timing in girls?. Pediatr Res 90, 176–183 (2021). https://doi.org/10.1038/s41390-020-01215-6
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DOI: https://doi.org/10.1038/s41390-020-01215-6
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