Abstract
Background
Low birth size (BS) and obesity have been associated with higher dehydroepiandrosterone sulfate (DHEAS) levels in childhood, insulin acting as a mediator, despite contradictory findings. To further explore these issues, we studied the associations between DHEAS, BS, adiposity, maternal characteristics, and cardiometabolic risk indicators, in participants of Generation XXI, a population-based birth cohort.
Methods
A sample of 700 children (mean age 7.1 yr) was randomly selected. Data on maternal characteristics, BS, body mass index (BMI), waist-to-height ratio, body fat (dual-energy X-ray absorptiometry), insulin, lipid profile, and high-sensitivity C-reactive protein were analyzed in relation to DHEAS.
Results
DHEAS was negatively associated with BS and positively associated with all adiposity indicators, with no sex differences. DHEAS was positively associated with insulinemia independently of the child’s BS or BMI. No significant association was found between DHEAS, maternal characteristics, lipid profile, or high-sensitivity C-reactive protein. Including insulin in the model did not affect the association between BS and DHEAS but reduced the magnitude of the BMI effect by 24% for boys and 30% for girls.
Conclusion
Higher DHEAS levels at 7 years old were associated with lower BS and higher adiposity. DHEAS levels were positively associated with insulinemia independently of BS or BMI.
Impact
-
Low birth weight and obesity have been associated with higher dehydroepiandrosterone sulfate (DHEAS) levels in prepuberty. Insulin has been suggested as a mediator, despite previous studies failing to show an association between DHEAS and insulin levels.
-
In a randomly selected population of 700 7-year-old children from the Generation XXI birth cohort, higher DHEAS levels were associated with a lower birth size and higher adiposity, with no sex differences.
-
DHEAS was positively related to insulinemia independently of the child’s birth size or body mass index.
-
No association was found between DHEAS and other cardiometabolic risk factors.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Prough, R. A., Clark, B. J. & Klinge, C. M. Novel mechanisms for DHEA action. J. Mol. Endocrinol. 56, R139–R155 (2016).
Ibanez, L., Dimartino-Nardi, J., Potau, N. & Saenger, P. Premature adrenarche–normal variant or forerunner of adult disease? Endocr. Rev. 21, 671–696 (2000).
Voutilainen, R. & Jaaskelainen, J. Premature adrenarche: etiology, clinical findings, and consequences. J. Steroid Biochem. Mol. Biol. 145, 226–236 (2015).
Utriainen, P., Laakso, S., Liimatta, J., Jaaskelainen, J. & Voutilainen, R. Premature adrenarche—a common condition with variable presentation. Horm. Res. Paediatr. 83, 221–231 (2015).
Rosenfield, R. L. Clinical review: identifying children at risk for polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 92, 787–796 (2007).
Ong, K. K. et al. Opposing influences of prenatal and postnatal weight gain on adrenarche in normal boys and girls. J. Clin. Endocrinol. Metab. 89, 2647–2651 (2004).
Nordman, H., Voutilainen, R., Antikainen, L. & Jaaskelainen, J. Prepubertal children born large for gestational age have lower serum DHEAS concentrations than those with a lower birth weight. Pediatr. Res. 82, 285–289 (2017).
Tenhola, S. et al. Increased adrenocortical and adrenomedullary hormonal activity in 12-year-old children born small for gestational age. J. Pediatr. 141, 477–482 (2002).
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. 94, 3696–3699 (2009).
Mericq, V., Pereira, A., Uauy, R. & Corvalan, C. Early BMI gain and later height growth predicts higher DHEAS concentrations in 7-year-old Chilean children. Horm. Res Paediatr. 87, 15–22 (2017).
Liimatta, J. et al. Tracking of serum DHEAS concentrations from age 1 to 6 years: a prospective cohort study. J. Endocr. Soc. 4, bvaa012 (2020).
Mantyselka, A. et al. Associations of dehydroepiandrosterone sulfate with cardiometabolic risk factors in prepubertal children. J. Clin. Endocrinol. Metab. 103, 2592–2600 (2018).
Corvalan, C., Uauy, R. & Mericq, V. Obesity is positively associated with dehydroepiandrosterone sulfate concentrations at 7 y in Chilean children of normal birth weight. Am. J. Clin. Nutr. 97, 318–325 (2013).
Kulle, A. E., Reinehr, T., Simic-Schleicher, G., Hornig, N. C. & Holterhus, P. M. Determination of 17OHPreg and DHEAS by LC-MS/MS: impact of age, sex, pubertal stage, and BMI on the Δ5 steroid pathway. J. Clin. Endocrinol. Metab. 102, 232–241 (2017).
Mantyselka, A. et al. The presentation of Adrenarche is sexually dimorphic and modified by body adiposity. J. Clin. Endocrinol. Metab. 99, 3889–3894 (2014).
Pereira, A., Iñiguez, G., Corvalan, C. & Mericq, V. High DHEAS is associated with earlier pubertal events in girls but not in boys. J. Endocr. Soc. 1, 800–808 (2017).
Ibanez, L. et al. Hyperinsulinemia and decreased insulin-like growth factor-binding protein-1 are common features in prepubertal and pubertal girls with a history of premature pubarche. J. Clin. Endocrinol. Metab. 82, 2283–2288 (1997).
Guercio, G., Rivarola, M. A., Chaler, E., Maceiras, M. & Belgorosky, A. Relationship between the GH/IGF-I Axis, insulin sensitivity, and adrenal androgens in normal prepubertal and pubertal boys. J. Clin. Endocrinol. Metab. 87, 1162–1169 (2002).
Guercio, G., Rivarola, M. A., Chaler, E., Maceiras, M. & Belgorosky, A. Relationship between the growth hormone/insulin-like growth factor-I axis, insulin sensitivity, and adrenal androgens in normal prepubertal and pubertal girls. J. Clin. Endocrinol. Metab. 88, 1389–1393 (2003).
Ibanez, L. et al. Postpubertal outcome in girls diagnosed of premature pubarche during childhood: increased frequency of functional ovarian hyperandrogenism. J. Clin. Endocrinol. Metab. 76, 1599–1603 (1993).
Larsen, P. S. et al. Pregnancy and birth cohort resources in Europe: a large opportunity for aetiological child health research. Paediatr. Perinat. Epidemiol. 27, 393–414 (2013).
Alves, E., Correia, S., Barros, H. & Azevedo, A. Prevalence of self-reported cardiovascular risk factors in Portuguese women: a survey after delivery. Int J. Public Health 57, 837–847 (2012).
Fenton, T. R. & Kim, J. H. A systematic review and meta-analysis to revise the Fenton growth chart for preterm infants. BMC Pediatr. 13, 59 (2013).
de Onis, M. et al. Development of a WHO growth reference for school-aged children and adolescents. Bull. World Health Organ. 85, 660–667 (2007).
Fernández, J. R. et al. Changes in pediatric waist circumference percentiles despite reported pediatric weight stabilization in the United States. Pediatr. Obes. 12, 347–355 (2017).
Friedewald, W. T., Levy, R. I. & Fredrickson, D. S. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin. Chem. 18, 499–502 (1972).
Matthews, D. R. et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28, 412–419 (1985).
Santos-Silva, R., Costa, C., Castro-Correia, C. & Fontoura, M. Clinical, biochemical and gender characteristics of 97 prepubertal children with premature adrenarche. J. Pediatr. Endocrinol. Metab. 32, 1247–1252 (2019).
Utriainen, P., Voutilainen, R. & Jaaskelainen, J. Continuum of phenotypes and sympathoadrenal function in premature adrenarche. Eur. J. Endocrinol. 160, 657–665 (2009).
Hammer, F. et al. No evidence for hepatic conversion of dehydroepiandrosterone (DHEA) sulfate to DHEA: in vivo and in vitro studies. J. Clin. Endocrinol. Metab. 90, 3600–3605 (2005).
Idkowiak, J. et al. Steroid sulfatase deficiency and androgen activation before and after puberty. J. Clin. Endocrinol. Metab. 101, 2545–2553 (2016).
Liimatta, J. et al. Serum androgen bioactivity is low in children with premature adrenarche. Pediatr. Res. 75, 645–650 (2014).
Diaz, A., Bhandari, S., Sison, C. & Vogiatzi, M. Characteristics of children with premature pubarche in the New York metropolitan area. Horm. Res. 70, 150–154 (2008).
Zukauskaite, S., Lasiene, D., Lasas, L., Urbonaite, B. & Hindmarsh, P. Onset of breast and pubic hair development in 1231 preadolescent Lithuanian schoolgirls. Arch. Dis. Child. 90, 932–936 (2005).
Cebeci, A. N. & Tas, A. Higher body fat and lower fat-free mass in girls with premature adrenarche. J. Clin. Res. Pediatr. Endocrinol. 7, 45–48 (2015).
Utriainen, P., Jääskeläinen, J., Romppanen, J. & Voutilainen, R. Childhood metabolic syndrome and its components in premature adrenarche. J. Clin. Endocrinol. Metab. 92, 4282–4285 (2007).
Genazzani, A. R., Pintor, C. & Corda, R. Plasma levels of gonadotropins, prolactin, thyroxine, and adrenal and gonadal steroids in obese prepubertal girls. J. Clin. Endocrinol. Metab. 47, 974–979 (1978).
Paterson, W. F. et al. Exaggerated adrenarche in a cohort of Scottish children: clinical features and biochemistry. Clin. Endocrinol. 72, 496–501 (2010).
Evliyaoglu, O., Berberoglu, M., Adiyaman, P., Aycan, Z. & Ocal, G. Evaluation of insulin resistance in Turkish girls with premature pubarche using the homeostasis assessment (HOMA) model. Turk. J. Pediatr. 49, 165–170 (2007).
Escobar, M. E., Gryngarten, M. G., Ballerini, M. G. & Ropelato, M. G. Clinical, hormonal and metabolic findings in argentinean girls with premature pubarche. Rev. Argent. Endocrinol. Metab. 44, 6–16 (2007).
Sagodi, L., Barkai, L., Tombacz, A. & Vamosi, I. Hyperinsulinemia, insulin-like growth factor-I, insulin-like growth factor-binding protein-1, and sex-hormone binding-globulin in prepubertal and pubertal girls with premature adrenarche. Orv. Hetil. 144, 67–72 (2003).
Akin, O. et al. Vitamin D insufficiency is related to premature adrenarche. Horm. Res. Paediatr. 86, 152–152 (2016).
Ibanez, L., Potau, N., Chacon, P., Pascual, C. & Carrascosa, A. Hyperinsulinaemia, dyslipaemia and cardiovascular risk in girls with a history of premature pubarche. Diabetologia 41, 1057–1063 (1998).
Ibanez, L. et al. Hyperinsulinemia in postpubertal girls with a history of premature pubarche and functional ovarian hyperandrogenism. J. Clin. Endocrinol. Metab. 81, 1237–1243 (1996).
Vuguin, P., Grinstein, G., Freeman, K., Saenger, P. & Nardi, J. D. Prediction models for insulin resistance in girls with premature adrenarche - The premature adrenarche insulin resistance score: PAIR score. Horm. Res. 65, 185–191 (2006).
DiMartino-Nardi, J. Pre- and postpubertal findings in premature adrenarche. J. Pediatr. Endocrinol. Metab. 13, 1265–1269 (2000).
Vuguin, P., Linder, B., Rosenfeld, R. G., Saenger, P. & DiMartino-Nardi, J. The roles of insulin sensitivity, insulin-like growth factor I (IGF-I), and IGF-binding protein-1 and -3 in the hyperandrogenism of African-American and Caribbean Hispanic girls with premature adrenarche. J. Clin. Endocrinol. Metab. 84, 2037–2042 (1999).
l’Allemand, D. et al. Insulin-like growth factors enhance steroidogenic enzyme and corticotropin receptor messenger ribonucleic acid levels and corticotropin steroidogenic responsiveness in cultured human adrenocortical cells. J. Clin. Endocrinol. Metab. 81, 3892–3897 (1996).
Hales, C. N. & Barker, D. J. The thrifty phenotype hypothesis. Br. Med Bull. 60, 5–20 (2001).
Ward, A. M. V., Syddall, H. E., Wood, P. J., Chrousos, G. P. & Phillips, D. I. W. Fetal programming of the Hypothalamic-Pituitary-Adrenal (HPA) axis: low birth weight and central HPA regulation. J. Clin. Endocrinol. Metab. 89, 1227–1233 (2004).
Ibanez, L., Potau, N., Francois, I. & de Zegher, F. Precocious pubarche, hyperinsulinism, and ovarian hyperandrogenism in girls: relation to reduced fetal growth. J. Clin. Endocrinol. Metab. 83, 3558–3562 (1998).
Likitmaskul, S. et al. ‘Exaggerated adrenarche’ in children presenting with premature adrenarche. Clin. Endocrinol. (Oxf.) 42, 265–272 (1995).
Rege, J. et al. 11-Ketotestosterone is the dominant circulating bioactive androgen during normal and premature adrenarche. J. Clin. Endocrinol. Metab. 103, 4589–4598 (2018).
Turcu, A. F. & Auchus, R. J. Clinical significance of 11-oxygenated androgens. Curr. Opin. Endocrinol. Diabetes Obes. 24, 252–259 (2017).
Wise-Oringer, B. K. et al. The unique role of 11-oxygenated C19 steroids in both premature adrenarche and premature pubarche. Horm. Res. Paediatr. 93, 460–469 (2020).
Acknowledgements
We gratefully acknowledge the families enrolled in Generation XXI for their kindness, all members of the research team for their enthusiasm and perseverance, as well as the participating hospitals and their staff for their help and support. Generation XXI was supported by the European Regional Development Fund (ERDF) through the Operational Programme Competitiveness and Internationalization and national funding from the Foundation for Science and Technology (FCT), Portuguese Ministry of Science, Technology and Higher Education under the project “HIneC: When do health inequalities start? Understanding the impact of childhood social adversity on health trajectories from birth to early adolescence” (POCI-01-0145-FEDER-029567; Reference PTDC/SAU-PUB/29567/2017). It is also supported by the Unidade de Investigação em Epidemiologia - Instituto de Saúde Pública da Universidade do Porto (EPIUnit) (UIDB/04750/2020), Administração Regional de Saúde Norte (Regional Department of Ministry of Health) and Fundação Calouste Gulbenkian. This study was also supported by a grant from the Portuguese Society of Paediatrics. A.C.S. is funded by FCT Investigator contracts IF/01060/2015.
Author information
Authors and Affiliations
Contributions
R.S.-S.: contributed to the design of the study and the acquisition of data, conducted the analysis, and interpretation of data, and drafted the article. M.F.: contributed to the conception of the study, the interpretation of data, and revised the article critically for relevant knowledgeable content. J.T.G.: conducted laboratory analysis and revised the article critically for relevant knowledgeable content. H.B.: assembled the cohort, contributed to the conception of the study, and revised the article critically for relevant knowledgeable content. A.C.S.: contributed to the conception of the study and the acquisition of data, participated in the analysis and interpretation of data, and revised the article critically for relevant knowledgeable content. All the authors have accepted responsibility for the entire content of this manuscript and approved submission.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing interests.
Patients’ consent
All the phases of the study complied with the Ethical Principles for Medical Research Involving Human Subjects expressed in the Declaration of Helsinki. The study was approved by the University of Porto Medical School/S. João Hospital Centre ethics committee and parents or legal representatives of the children signed informed consent at the baseline and all the subsequent follow-up evaluations. Children gave their oral assent in all phases of the study.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Santos-Silva, R., Fontoura, M., Guimarães, J.T. et al. Association of dehydroepiandrosterone sulfate, birth size, adiposity and cardiometabolic risk factors in 7-year-old children. Pediatr Res 91, 1897–1905 (2022). https://doi.org/10.1038/s41390-021-01706-0
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41390-021-01706-0
This article is cited by
-
Body composition in prepubertal children with idiopathic premature adrenarche: implications for cardiometabolic health
Pediatric Research (2025)
-
Metabolomic signatures for blood pressure from early to late adolescence: findings from a U.S. cohort
Metabolomics (2024)
-
Birth size and the serum level of biological age markers in men
Scientific Reports (2023)
-
Association between dehydroepiandrosterone sulphate levels at 7 years old and bone mineral density at 10 years old: a prospective cohort study
European Journal of Pediatrics (2022)
