{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,13]],"date-time":"2025-11-13T02:06:16Z","timestamp":1762999576503,"version":"build-2065373602"},"reference-count":24,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2020,5,23]],"date-time":"2020-05-23T00:00:00Z","timestamp":1590192000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Britisch Heart Foundation Programme Grant","award":["RA and RBW"],"award-info":[{"award-number":["RA and RBW"]}]},{"DOI":"10.13039\/100010269","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["BRW"],"award-info":[{"award-number":["BRW"]}],"id":[{"id":"10.13039\/100010269","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003246","name":"Nederlandse Organisatie voor Wetenschappelijk Onderzoek","doi-asserted-by":"publisher","award":["51.02.060, 668.772, 480-04-004, 56-464-14192"],"award-info":[{"award-number":["51.02.060, 668.772, 480-04-004, 56-464-14192"]}],"id":[{"id":"10.13039\/501100003246","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001722","name":"Koninklijke Nederlandse Akademie van Wetenschappen","doi-asserted-by":"publisher","award":["PAH\/6635"],"award-info":[{"award-number":["PAH\/6635"]}],"id":[{"id":"10.13039\/501100001722","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Childhood obesity is associated with alterations in hypothalamus\u2013pituitary\u2013adrenal (HPA) axis activity. However, it is unknown whether these alterations are a cause or a consequence of obesity. This study aimed to explore the temporal relationship between cortisol production and metabolism, and body mass index (BMI). This prospective follow-up study included 218 children (of whom 50% were male), born between 1995 and 1996, who were assessed at the ages of 9, 12 and 17 years. Morning urine samples were collected for assessment of cortisol metabolites by gas chromatography-tandem mass spectrometry, enabling the calculation of cortisol metabolite excretion rate and cortisol metabolic pathways. A cross-lagged regression model was used to determine whether BMI at various ages during childhood predicted later cortisol production and metabolism parameters, or vice versa. The cross-lagged regression coefficients showed that BMI positively predicted cortisol metabolite excretion (p = 0.03), and not vice versa (p = 0.33). In addition, BMI predicted the later balance of 11\u03b2-hydroxysteroid dehydrogenase (HSD) activities (p = 0.07), and not vice versa (p = 0.55). Finally, cytochrome P450 3A4 activity positively predicted later BMI (p = 0.01). Our study suggests that changes in BMI across the normal range predict alterations in HPA axis activity. Therefore, the alterations in HPA axis activity as observed in earlier studies among children with obesity may be a consequence rather than a cause of increased BMI.<\/jats:p>","DOI":"10.3390\/nu12051525","type":"journal-article","created":{"date-parts":[[2020,5,25]],"date-time":"2020-05-25T06:43:40Z","timestamp":1590389020000},"page":"1525","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Exploring the Temporal Relation between Body Mass Index and Corticosteroid Metabolite Excretion in Childhood"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2848-9533","authenticated-orcid":false,"given":"Britt J.","family":"Van Keulen","sequence":"first","affiliation":[{"name":"Emma Children\u2019s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Endocrinology, Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Conor V.","family":"Dolan","sequence":"additional","affiliation":[{"name":"Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, Van der Boechorststraat 7-9, 1081 BT, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruth","family":"Andrew","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Science, University of Edinburgh, Queen\u2019s Medical Research Institute, 47, Little France Crescent, Edinburgh EH16 4TJ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2416-1648","authenticated-orcid":false,"given":"Brian R.","family":"Walker","sequence":"additional","affiliation":[{"name":"Centre for Cardiovascular Science, University of Edinburgh, Queen\u2019s Medical Research Institute, 47, Little France Crescent, Edinburgh EH16 4TJ, UK"},{"name":"Institute of Genetic Medicine, Newcastle University, Central Pkwy, Newcastle upon Tyne NE1 3BZ, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hilleke E.","family":"Hulshoff Pol","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, University Medical Center Utrecht, Brain Center, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dorret I.","family":"Boomsma","sequence":"additional","affiliation":[{"name":"Netherlands Twin Register, Department of Biological Psychology, Vrije Universiteit Amsterdam, Van der Boechorststraat 7-9, 1081 BT, Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joost","family":"Rotteveel","sequence":"additional","affiliation":[{"name":"Emma Children\u2019s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Endocrinology, Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6589-9788","authenticated-orcid":false,"given":"Martijn J.J.","family":"Finken","sequence":"additional","affiliation":[{"name":"Emma Children\u2019s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric Endocrinology, Amsterdam, De Boelelaan 1117, 1081 HV Amsterdam, The Netherlands"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.tem.2009.10.004","article-title":"Stress-induced obesity and the emotional nervous system","volume":"21","author":"Dallman","year":"2010","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1139","DOI":"10.1152\/physrev.00020.2012","article-title":"11beta-hydroxysteroid dehydrogenases: Intracellular gate-keepers of tissue glucocorticoid action","volume":"93","author":"Chapman","year":"2013","journal-title":"Physiol. Rev."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Perez, J.H., Swanson, R.E., Lau, H.J., Cheah, J., Bishop, V.R., Snell, K.R.S., Reid, A.M.A., Meddle, S.L., Wingfield, J.C., and Krause, J.S. (2020). Tissue-specific expression of 11beta-HSD and its effects on plasma corticosterone during the stress response. J. Exp. Biol., 223.","DOI":"10.1242\/jeb.209346"},{"key":"ref_4","first-page":"107","article-title":"Cortisol and its relation to insulin resistance before and after weight loss in obese children","volume":"62","author":"Reinehr","year":"2004","journal-title":"Horm. Res."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"344","DOI":"10.4274\/jcrpe.4802","article-title":"Is There an Association Between Cortisol and Hypertension in Overweight or Obese Children?","volume":"9","author":"Wirix","year":"2017","journal-title":"J. Clin. Res. Pediatr. Endocrinol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2391","DOI":"10.1210\/jc.2013-4398","article-title":"Relationships between 24-hour urinary free cortisol concentrations and metabolic syndrome in obese children","volume":"99","author":"Reinehr","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1080\/10253890.2017.1303830","article-title":"Hair cortisol concentrations exhibit a positive association with salivary cortisol profiles and are increased in obese prepubertal girls","volume":"20","author":"Papafotiou","year":"2017","journal-title":"Stress"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4415","DOI":"10.1210\/jc.2009-2105","article-title":"A nonlinear relationship of generalized and central obesity with diurnal cortisol secretion in the Whitehall II study","volume":"95","author":"Kumari","year":"2010","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1210\/jcem-24-9-832","article-title":"Cortisol Metabolism in Obesity","volume":"24","author":"Dunkelman","year":"1964","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"4329","DOI":"10.1210\/jc.2016-1754","article-title":"Steroid Metabolomic Disease Signature of Nonsyndromic Childhood Obesity","volume":"101","author":"Gawlik","year":"2016","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"E1022","DOI":"10.1210\/jc.2013-1173","article-title":"Steroid hormone profiles in prepubertal obese children before and after weight loss","volume":"98","author":"Reinehr","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1038\/s41366-019-0447-4","article-title":"Longitudinal associations between overweight\/obesity and stress biology in low-income children","volume":"44","author":"Doom","year":"2020","journal-title":"Int. J. Obes. (Lond)"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"285","DOI":"10.1210\/jc.2013-2924","article-title":"Increased scalp hair cortisol concentrations in obese children","volume":"99","author":"Veldhorst","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"van Keulen, B.J., Dolan, C.V., Andrew, R., Walker, B.R., Hulshoff Pol, H.E., Boomsma, D.I., Rotteveel, J., and Finken, M.J.J. (2020). Heritability of Cortisol Production and Metabolism Throughout Adolescence. J. Clin. Endocrinol. Metab., 105.","DOI":"10.1210\/clinem\/dgz016"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1375\/twin.9.6.849","article-title":"Netherlands Twin Register: From twins to twin families","volume":"9","author":"Boomsma","year":"2006","journal-title":"Twin Res. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"401","DOI":"10.1375\/136905202320906174","article-title":"Netherlands Twin Register: A focus on longitudinal research","volume":"5","author":"Boomsma","year":"2002","journal-title":"Twin Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1017\/thg.2012.4","article-title":"Brain SCALE: Brain structure and cognition: An adolescent longitudinal twin study into the genetic etiology of individual differences","volume":"15","author":"Brouwer","year":"2012","journal-title":"Twin Res. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1093\/cercor\/bhy005","article-title":"Genetic Influences on the Development of Cerebral Cortical Thickness During Childhood and Adolescence in a Dutch Longitudinal Twin Sample: The Brainscale Study","volume":"29","author":"Teeuw","year":"2019","journal-title":"Cereb. Cortex"},{"key":"ref_19","unstructured":"Sch\u00f6nbeck, Y., and van Buuren, S. (2010). Vijfde Landelijke Groeistudie, TNO."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.ab.2017.09.002","article-title":"Gas chromatography tandem mass spectrometry offers advantages for urinary steroids analysis","volume":"538","author":"Homer","year":"2017","journal-title":"Anal. Biochem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1017\/thg.2020.6","article-title":"Long-Term Stability of Cortisol Production and Metabolism Throughout Adolescence: Longitudinal Twin Study","volume":"23","author":"Dolan","year":"2020","journal-title":"Twin Res. Hum. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1017\/thg.2018.23","article-title":"Establishing a Twin Register: An Invaluable Resource for (Behavior) Genetic, Epidemiological, Biomarker, and \u2019Omics\u2019 Studies","volume":"21","author":"Odintsova","year":"2018","journal-title":"Twin Res. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1007\/s00125-014-3228-6","article-title":"Tissue-specific dysregulation of cortisol regeneration by 11betaHSD1 in obesity: Has it promised too much?","volume":"57","author":"Stomby","year":"2014","journal-title":"Diabetologia"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1152\/physrev.00033.2011","article-title":"Pathophysiology of human visceral obesity: An update","volume":"93","author":"Tchernof","year":"2013","journal-title":"Physiol. Rev."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/5\/1525\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:31:54Z","timestamp":1760175114000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/12\/5\/1525"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,23]]},"references-count":24,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2020,5]]}},"alternative-id":["nu12051525"],"URL":"https:\/\/doi.org\/10.3390\/nu12051525","relation":{},"ISSN":["2072-6643"],"issn-type":[{"type":"electronic","value":"2072-6643"}],"subject":[],"published":{"date-parts":[[2020,5,23]]}}}