{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T04:25:55Z","timestamp":1788323155950,"version":"build-2803163510"},"reference-count":91,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T00:00:00Z","timestamp":1618963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Dehydroepiandrosterone (DHEA) and its sulfated metabolite (DHEAS) are dynamically regulated before birth and the onset of puberty. Yet, the origins and purpose of increasing DHEA[S] in postnatal development remain elusive. Here, we draw attention to this pre-pubertal surge from the adrenal gland\u2014the adrenarche\u2014and discuss whether this is the result of intra-adrenal gene expression specifically affecting the zona reticularis (ZR), if the ZR is influenced by the hypothalamic-pituitary axis, and the possible role of spino-sympathetic innervation in prompting increased ZR activity. We also discuss whether neural DHEA[S] synthesis is coordinately regulated with the developing adrenal gland. We propose that DHEA[S] is crucial in the brain maturation of humans prior to and during puberty, and suggest that the function of the adrenarche is to modulate, adapt and rewire the pre-adolescent brain for new and ever-changing social challenges. The etiology of DHEA[S] synthesis, neurodevelopment and recently described 11-keto and 11-oxygenated androgens are difficult to investigate in humans owing to: (i) ethical restrictions on mechanistic studies, (ii) the inability to predict which individuals will develop specific mental characteristics, and (iii) the difficulty of conducting retrospective studies based on perinatal complications. We discuss new opportunities for animal studies to overcome these important issues.<\/jats:p>","DOI":"10.3390\/ijms22094296","type":"journal-article","created":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T12:47:07Z","timestamp":1619009227000},"page":"4296","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["The Enigma of the Adrenarche: Identifying the Early Life Mechanisms and Possible Role in Postnatal Brain Development"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4463-9378","authenticated-orcid":false,"given":"Angela L.","family":"Cumberland","sequence":"first","affiliation":[{"name":"School of Health &amp; Biomedical Sciences, Bundoora Campus, RMIT University, Melbourne, VIC 3083, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan J.","family":"Hirst","sequence":"additional","affiliation":[{"name":"Mothers and Babies Research Centre, School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW 2308, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilio","family":"Badoer","sequence":"additional","affiliation":[{"name":"School of Health &amp; Biomedical Sciences, Bundoora Campus, RMIT University, Melbourne, VIC 3083, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7163-5957","authenticated-orcid":false,"given":"Stefan A.","family":"Wudy","sequence":"additional","affiliation":[{"name":"Steroid Research &amp; Mass Spectrometry Laboratory, Division of Pediatric Endocrinology &amp; Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, 35392 Giessen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7823-8797","authenticated-orcid":false,"given":"Ronda F.","family":"Greaves","sequence":"additional","affiliation":[{"name":"School of Health &amp; Biomedical Sciences, Bundoora Campus, RMIT University, Melbourne, VIC 3083, Australia"},{"name":"Murdoch Children\u2019s Research Institute, Parkville, VIC 3052, Australia"},{"name":"Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margaret","family":"Zacharin","sequence":"additional","affiliation":[{"name":"Murdoch Children\u2019s Research Institute, Parkville, VIC 3052, Australia"},{"name":"Department of Paediatrics, University of Melbourne, Parkville, VIC 3052, Australia"},{"name":"Department of Endocrinology, Royal Children\u2019s Hospital, Parkville, VIC 3052, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4958-6140","authenticated-orcid":false,"given":"David W.","family":"Walker","sequence":"additional","affiliation":[{"name":"School of Health &amp; Biomedical Sciences, Bundoora Campus, RMIT University, Melbourne, VIC 3083, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Campbell, B. 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