ESPE Yearbook of Paediatric Endocrinology

Brief Summary: The mechanism by which suboptimal intrauterine growth and low birth weight for gestational age may lead to postnatal metabolic risks has not been well established. This narrative review summarizes recent studies on the association between early infant growth, timing of puberty, and metabolic risks, thus expanding our knowledge of the underlying pathophysiology.

Comment: Early compensatory infantile growth in children born small for gestational age (SGA), i.e. involving abnormal intrauterine or prenatal growth and/or early accelerated postnatal growth in children with premature adrenarche (PA), is associated with an increased propensity for cardiometabolic risk factors or metabolic syndrome phenotype later in life (1). Changes in metabolic programming by leptin signaling, epigenetic reprogramming of mesenchymal stem cells or alteration of DNA methylation have been proposed, while genetic or maternal factors that are associated with either the above described abnormal growth patterns or the appearance of metabolic syndrome in adulthood have also been studied (2-4). In addition, if malnutrition in prenatal life is followed by abundant nutrition after birth, it may induce metabolic programming of the fetal organs that predisposes them to insulin resistance and metabolic syndrome (“thrifty phenotype hypothesis”) (5). Further research is needed to establish the best approach to prevent the metabolic programming favoring metabolic risks during the nutritional replenish phase.

The common initial pathophysiologic pathway seems to involve early adrenal maturation (6). Adrenarche begins in early childhood, due to maturation of the adrenal cortex zona reticularis, with a concomitant gradual increase in adrenal androgen production (7). The most sensitive biochemical marker for adrenarche is sulfated dehydroepiandrosterone (DHEA-S) concentrations (8). DHEA-S is produced in the fetal adrenal gland, its concentrations are high at birth but then they rapidly decline during infancy and rise again gradually at onset of adrenarche, reaching peak level in the second decade of life (6). This DHEA-S elevation is also a marker of PA that can clinically be defined by the appearance of symptoms (adult body odor, oily skin, acne, pubic and axillary hair) at an earlier than the expected age (6). Of note, children born SGA, especially after catch-up growth, have elevated DHEA-S concentrations between 6 and 8 years of age and are more prone to develop PA (9).

Children born SGA are at increased risk of early puberty, associated with early maturation of the zona reticularis and increased DHEA-S following early catch-up growth (10). This hypothesis has been extensively studied and it is possibly mediated by DHEA-S and other adrenal androgens (11, 12). In addition, investigations using liquid chromatography-tandem mass spectroscopy (LC-MS/MS) have broadened the traditional androgen repertoire to include other androgens with higher binding capacity to the androgen receptor (13).

Earlier age of pubertal onset is associated with high BMI in childhood, while PA may be independently associated with increased cardiometabolic risk (14). The hypothesis of this 3-way reciprocal association potentially links increased body weight with early onset adrenarche or/and puberty with cardiometabolic risk. The pathogenetic starting point (primum movens) remains to be elucidated, with novel studies and approaches that include detailed CNS functional imaging (functional MRI) (15). Underlying genetic variants may explain the association between adrenal androgens and metabolic risks.

In summary, studies agree that pubertal timing is a risk factor, which independently influences several metabolic disease-related traits, including the degree of obesity, serum lipids, and insulin, both in adult females and males. The observed connection between pubertal timing and adult metabolic outcomes implies that mechanisms that advance puberty may also contribute to adult metabolic disorders. As adult metabolic disease risk is shaped over the life course, understanding this link and the critical developmental events may highlight important pathogenic mechanisms. They may also inform more specific individualised prevention strategies. Future studies, including birth history, early infantile growth, various adrenal androgens, and timing of puberty are required to assess metabolic disease risks in addition to suitable animal models to study the sequence of SGA, adrenal maturation and metabolic disorders.

References: 1. Nordman H, Jaaskelainen J, Voutilainen R. Birth Size as a Determinant of Cardiometabolic Risk Factors in Children. Horm Res Paediatr. 2020; 93(3): 144-53.2. Lewandowski KC, Biesiada L, Grzesiak M, Sakowicz A. C-Peptide and leptin system in dichorionic, small and appropriate for gestational age twins-possible link to metabolic programming? Nutr Diabetes. 2020; 10(1): 29.3. Peeters S, Declerck K, Thomas M, Boudin E, Beckers D, Chivu O, et al. DNA Methylation Profiling and Genomic Analysis in 20 Children with Short Stature Who Were Born Small for Gestational Age. J Clin Endocrinol Metab. 2020; 105(12).4. Beaumont RN, Kotecha SJ, Wood AR, Knight BA, Sebert S, McCarthy MI, et al. Common maternal and fetal genetic variants show expected polygenic effects on risk of small- or large-for-gestational-age (SGA or LGA), except in the smallest 3% of babies. PLoS Genet. 2020; 16(12): e1009191.5. Hales CN, Barker DJ. The thrifty phenotype hypothesis. Br Med Bull. 2001; 60: 5-20.6. Rosenfield RL. Normal and Premature Adrenarche. Endocr Rev. 2021; 42(6): 783-814.7. Palmert MR, Hayden DL, Mansfield MJ, Crigler JF, Jr., Crowley WF, Jr., Chandler DW, et al. The longitudinal study of adrenal maturation during gonadal suppression: evidence that adrenarche is a gradual process. J Clin Endocrinol Metab. 2001; 86(9): 4536-42.8. Rege J, Turcu AF, Kasa-Vubu JZ, Lerario AM, Auchus GC, Auchus RJ, et al. 11-Ketotestosterone Is the Dominant Circulating Bioactive Androgen During Normal and Premature Adrenarche. J Clin Endocrinol Metab. 2018; 103(12): 4589-98.9. Ibanez L, Lopez-Bermejo A, Diaz M, Suarez L, de Zegher F. Low-birth weight children develop lower sex hormone binding globulin and higher dehydroepiandrosterone sulfate levels and aggravate their visceral adiposity and hypoadiponectinemia between six and eight years of age. J Clin Endocrinol Metab. 2009; 94(10): 3696-9.10. Iniguez G, Ong K, Bazaes R, Avila A, Salazar T, Dunger D, et al. Longitudinal changes in insulin-like growth factor-I, insulin sensitivity, and secretion from birth to age three years in small-for-gestational-age children. J Clin Endocrinol Metab. 2006; 91(11): 4645-9.11. Mantyselka A, Jaaskelainen J, Eloranta AM, Vaisto J, Voutilainen R, Ong K, et al. Associations of lifestyle factors with serum dehydroepiandrosterone sulphate and insulin-like growth factor-1 concentration in prepubertal children. Clin Endocrinol (Oxf). 2018; 88(2): 234-42.12. Liimatta J, Utriainen P, Laitinen T, Voutilainen R, Jaaskelainen J. Cardiometabolic Risk Profile Among Young Adult Females with a History of Premature Adrenarche. J Endocr Soc. 2019; 3(10): 1771-83.13. Rege J, Nakamura Y, Satoh F, Morimoto R, Kennedy MR, Layman LC, et al. Liquid chromatography-tandem mass spectrometry analysis of human adrenal vein 19-carbon steroids before and after ACTH stimulation. J Clin Endocrinol Metab. 2013; 98(3): 1182-8.14. Widen E, Silventoinen K, Sovio U, Ripatti S, Cousminer DL, Hartikainen AL, et al. Pubertal timing and growth influences cardiometabolic risk factors in adult males and females. Diabetes Care. 2012; 35(4): 850-6.15. Tzounakou AM, Stathori G, Paltoglou G, Valsamakis G, Mastorakos G, Vlahos NF, Charmandari E. Childhood Obesity, Hypothalamic Inflammation, and the Onset of Puberty: A Narrative Review. Nutrients. 2024;16(11).