{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T00:45:19Z","timestamp":1760143519687,"version":"build-2065373602"},"reference-count":45,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2024,2,17]],"date-time":"2024-02-17T00:00:00Z","timestamp":1708128000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["HE 3557\/1-1"],"award-info":[{"award-number":["HE 3557\/1-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"name":"University Medicine Giessen","award":["HE 3557\/1-1"],"award-info":[{"award-number":["HE 3557\/1-1"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Adrenal function is essential for survival and well-being of preterm babies. In addition to glucocorticoids, it has been hypothesized that C19-steroids (DHEA-metabolites) from the fetal zone of the adrenal gland may play a role as endogenous neuroprotective steroids. In 39 term-born (\u226537 weeks gestational age), 42 preterm (30\u201336 weeks) and 51 early preterm (&lt;30 weeks) infants 38 steroid metabolites were quantified by GC-MS in 24-h urinary samples. In each gestational age group, three distinctive cluster were identified by pattern analysis (k-means clustering). Individual steroidal fingerprints and clinical phenotype were analyzed at the 3rd day of life. Overall, the excretion rates of C21-steroids (glucocorticoid precursors, cortisol, and cortisone metabolites) were low (&lt;99 \u03bcg\/kg body weight\/d) whereas the excretion rates of C19-steroids were up to 10 times higher. There was a shift to higher excretion rates of C19-steroids in both preterm groups compared to term infants but only minor differences in the distribution of C21-steroids. Comparable metabolic patterns were found between gestational age groups: Cluster 1 showed mild elevation of C21- and C19-steroids with the highest incidence of neonatal morbidities in term and severe intraventricular hemorrhage in early preterm infants. In cluster 2 lowest excretion in general was noted but no clinically unique phenotype. Cluster 3 showed highest elevation of C21-steroids and C19-steroids but no clinically unique phenotype. Significant differences in steroid metabolism between clusters are only partly reflected by gestational age and disease severity. In early preterm infants, higher excretion rates of glucocorticoids and their precursors were associated with severe cerebral hemorrhage. High excretion rates of C19-steroids in preterm infants may indicate a biological significance.<\/jats:p>","DOI":"10.3390\/biom14020235","type":"journal-article","created":{"date-parts":[[2024,2,19]],"date-time":"2024-02-19T05:39:56Z","timestamp":1708321196000},"page":"235","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Steroid Metabolomic Signature in Term and Preterm Infants"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5260-264X","authenticated-orcid":false,"given":"Matthias","family":"Heckmann","sequence":"first","affiliation":[{"name":"Department of Neonatology and Pediatric Intensive Care, University Medicine Greifswald, Sauerbruchstra\u00dfe, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-3114-4741","authenticated-orcid":false,"given":"Anna S.","family":"Runkel","sequence":"additional","affiliation":[{"name":"Department of Neonatology and Pediatric Intensive Care, University Medicine Greifswald, Sauerbruchstra\u00dfe, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Donna E.","family":"Sunny","sequence":"additional","affiliation":[{"name":"Department of Neonatology and Pediatric Intensive Care, University Medicine Greifswald, Sauerbruchstra\u00dfe, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michaela F.","family":"Hartmann","sequence":"additional","affiliation":[{"name":"Paediatric Endocrinology & Diabetology, Laboratory for Translational Hormone Analytics, Steroid Research & Mass Spectrometry Unit, Center of Child and Adolescent Medicine, Justus Liebig University, 35392 Giessen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0154-7353","authenticated-orcid":false,"given":"Till","family":"Ittermann","sequence":"additional","affiliation":[{"name":"Institute for Community Medicine, University Medicine Greifswald, 17475 Greifswald, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7163-5957","authenticated-orcid":false,"given":"Stefan A.","family":"Wudy","sequence":"additional","affiliation":[{"name":"Paediatric Endocrinology & Diabetology, Laboratory for Translational Hormone Analytics, Steroid Research & Mass Spectrometry Unit, Center of Child and Adolescent Medicine, Justus Liebig University, 35392 Giessen, Germany"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.3389\/fped.2016.00023","article-title":"Mortality and Major. Morbidity of Very-Low-Birth-Weight. Infants in Germany 2008\u20132012: A Report Based on Administrative Data","volume":"4","author":"Jeschke","year":"2016","journal-title":"Front. Pediatr."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e20180933","DOI":"10.1542\/peds.2018-0933","article-title":"Survival and Impairment of Extremely Premature Infants: A Meta-analysis","volume":"143","author":"Myrhaug","year":"2019","journal-title":"Pediatrics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"317","DOI":"10.1210\/er.2010-0001","article-title":"Development and function of the human fetal adrenal cortex: A key component in the feto-placental unit","volume":"32","author":"Ishimoto","year":"2011","journal-title":"Endocr. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3111","DOI":"10.1210\/clinem\/dgac482","article-title":"The Androgen Metabolome of Preterm Infants Reflects Fetal Adrenal Gland Involution","volume":"107","author":"Fluck","year":"2022","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1515\/JPEM.2006.19.11.1303","article-title":"Persistent high activity of the fetal adrenal cortex in preterm infants: Is there a clinical significance?","volume":"19","author":"Heckmann","year":"2006","journal-title":"J. Pediatr. Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1203\/00006450-199812000-00011","article-title":"Adrenal function in preterm infants: ACTH may not be the sole regulator of the fetal zone","volume":"44","author":"Midgley","year":"1998","journal-title":"Pediatr. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.mvr.2014.07.010","article-title":"Combination of dehydroepiandrosterone and orthovanadate administration reduces intestinal leukocyte recruitment in models of experimental sepsis","volume":"95","author":"Pavlovic","year":"2014","journal-title":"Microvasc. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1038\/pr.2013.73","article-title":"Beneficial effect of dehydroepiandrosterone on pulmonary hypertension in a rodent model of pulmonary hypertension in infants","volume":"74","author":"Quignard","year":"2013","journal-title":"Pediatr. Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/jcbfm.2008.118","article-title":"DHEA-neuroprotection and -neurotoxicity after transient cerebral ischemia in rats","volume":"29","author":"Li","year":"2009","journal-title":"J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow. Metab."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"3202","DOI":"10.1073\/pnas.0307325101","article-title":"Mitotic and neurogenic effects of dehydroepiandrosterone (DHEA) on human neural stem cell cultures derived from the fetal cortex","volume":"101","author":"Suzuki","year":"2004","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"556","DOI":"10.1016\/j.bcp.2015.08.093","article-title":"Role of sex steroids and their receptors in human preterm infants: Impacts on future treatment strategies for cerebral development","volume":"98","author":"Hubner","year":"2015","journal-title":"Biochem. Pharmacol."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Sunny, D.E., Hammer, E., Ittermann, T., Kruger, E.L., Hubner, S., Hartmann, M.F., Wudy, S.A., Volker, U., and Heckmann, M. (2021). Fetal Zone Steroids and Estrogen Show Sex Specific Effects on Oligodendrocyte Precursor Cells in Response to Oxidative Damage. Int J Mol Sci, 12.","DOI":"10.3390\/ijms22126586"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"S44","DOI":"10.1038\/jp.2009.24","article-title":"Relative adrenal insufficiency in the preterm and term infant","volume":"29","author":"Fernandez","year":"2009","journal-title":"J. Perinatol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Van den Berghe, G., Teblick, A., Langouche, L., and Gunst, J. (2022). The hypothalamus-pituitary-adrenal axis in sepsis- and hyperinflammation-induced critical illness: Gaps in current knowledge and future translational research directions. EBioMedicine, 84.","DOI":"10.1016\/j.ebiom.2022.104284"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.1056\/NEJMoa1214969","article-title":"Reduced cortisol metabolism during critical illness","volume":"368","author":"Boonen","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3315","DOI":"10.1210\/jc.2012-4280","article-title":"How changes in affinity of corticosteroid-binding globulin modulate free cortisol concentration","volume":"98","author":"Chan","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1007\/s00134-009-1480-x","article-title":"Serum free cortisol index, free cortisol, and total cortisol in critically ill children","volume":"35","author":"Poomthavorn","year":"2009","journal-title":"Intensive Care Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2057","DOI":"10.1210\/clinem\/dgac201","article-title":"Critical Illness-induced Corticosteroid Insufficiency: What It Is Not and What It Could Be","volume":"107","author":"Teblick","year":"2022","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"5737","DOI":"10.1210\/jc.2005-0870","article-title":"Cortisol production rates in preterm infants in relation to growth and illness: A non invasive prospective study using GC-MS","volume":"90","author":"Heckmann","year":"2005","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1159\/000285571","article-title":"Maturation of adrenal function determined by urinary glucocorticoid steroid excretion rates in preterm infants of more than 30 weeks of gestational age","volume":"98","author":"Grofer","year":"2010","journal-title":"Neonatology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"e3725","DOI":"10.1210\/clinem\/dgab194","article-title":"Impact of Gestational and Postmenstrual Age on Excretion of Fetal Zone Steroids in Preterm Infants Determined by Gas Chromatography-Mass Spectrometry","volume":"106","author":"Ruhnau","year":"2021","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1016\/S0022-3476(78)80282-0","article-title":"Incidence and evolution of subependymal and intraventricular hemorrhage: A study of infants with birth weights less than 1500 gm","volume":"92","author":"Papile","year":"1978","journal-title":"J. Pediatr."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1542\/peds.91.3.617","article-title":"Score for Neonatal Acute Physiology: A physiologic severity index for neonatal intensive care","volume":"91","author":"Richardson","year":"1993","journal-title":"Pediatrics"},{"key":"ref_24","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_25","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1038\/jp.2009.191","article-title":"Early cortisol values and long-term outcomes in extremely low birth weight infants","volume":"30","author":"Aucott","year":"2010","journal-title":"J. Perinatol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1203\/PDR.0b013e31821764b1","article-title":"A prospective longitudinal study to estimate the \u201cadjusted cortisol percentile\u201d in preterm infants","volume":"69","author":"Ng","year":"2011","journal-title":"Pediatr. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.jpeds.2020.12.057","article-title":"Association between Baseline Cortisol Serum Concentrations and the Effect of Prophylactic Hydrocortisone in Extremely Preterm Infants","volume":"234","author":"Renolleau","year":"2021","journal-title":"J. Pediatr."},{"key":"ref_28","first-page":"791","article-title":"Endocrine Functions of the Human Fetoplacental Unit","volume":"23","author":"Diczfalusy","year":"1964","journal-title":"Fed. Proc."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1210\/jcem-26-7-751","article-title":"Placental estrogen biosynthesis during human pregnancy","volume":"26","author":"Siiteri","year":"1966","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1186\/cc1530","article-title":"Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: A sign of exhausted adrenal reserve?","volume":"6","author":"Beishuizen","year":"2002","journal-title":"Crit. Care"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2548","DOI":"10.1210\/jc.2005-2258","article-title":"Dissociation of serum dehydroepiandrosterone and dehydroepiandrosterone sulfate in septic shock","volume":"91","author":"Arlt","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1210\/clinem\/dgz302","article-title":"Mapping the Steroid Response to Major Trauma From Injury to Recovery: A Prospective Cohort Study","volume":"105","author":"Foster","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_33","first-page":"3217","article-title":"Five-day pulsatile gonadotropin-releasing hormone administration unveils combined hypothalamic-pituitary-gonadal defects underlying profound hypoandrogenism in men with prolonged critical illness","volume":"86","author":"Weekers","year":"2001","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s41038-019-0158-z","article-title":"Dehydroepiandrosterone: A potential therapeutic agent in the treatment and rehabilitation of the traumatically injured patient","volume":"7","author":"Bentley","year":"2019","journal-title":"Burns Trauma."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"127","DOI":"10.1016\/j.jsbmb.2009.12.016","article-title":"Dehydroepiandrosterone as a regulator of immune cell function","volume":"120","author":"Hazeldine","year":"2010","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"e040823","DOI":"10.1136\/bmjopen-2020-040823","article-title":"A prospective, phase II, single-centre, cross-sectional, randomised study investigating Dehydroepiandrosterone supplementation and its Profile in Trauma: ADaPT","volume":"11","author":"Bentley","year":"2021","journal-title":"BMJ Open"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1016\/j.burns.2015.08.023","article-title":"The efficacy and safety of oxandrolone treatment for patients with severe burns: A systematic review and meta-analysis","volume":"42","author":"Li","year":"2016","journal-title":"Burns J. Int. Soc. Burn. Inj."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1016\/S0039-128X(96)00161-4","article-title":"Role of growth factors in the developmental regulation of the human fetal adrenal cortex","volume":"62","author":"Mesiano","year":"1997","journal-title":"Steroids"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"775","DOI":"10.1542\/peds.2007-2252","article-title":"Do cortisol concentrations predict short-term outcomes in extremely low birth weight infants?","volume":"122","author":"Aucott","year":"2008","journal-title":"Pediatrics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1016\/S0140-6736(16)00202-6","article-title":"Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): A double-blind, placebo-controlled, multicentre, randomised trial","volume":"387","author":"Baud","year":"2016","journal-title":"Lancet"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1001\/jama.2018.21443","article-title":"Effect of Hydrocortisone Therapy Initiated 7 to 14 Days After Birth on Mortality or Bronchopulmonary Dysplasia Among Very Preterm Infants Receiving Mechanical Ventilation: A Randomized Clinical Trial","volume":"321","author":"Onland","year":"2019","journal-title":"JAMA"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1121","DOI":"10.1056\/NEJMoa2114897","article-title":"Hydrocortisone to Improve Survival without Bronchopulmonary Dysplasia","volume":"386","author":"Watterberg","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1210\/clinem\/dgaa133","article-title":"Prevention of Adrenal Crisis: Cortisol Responses to Major Stress Compared to Stress Dose Hydrocortisone Delivery","volume":"105","author":"Prete","year":"2020","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"e2217812","DOI":"10.1001\/jamanetworkopen.2022.17812","article-title":"Cortisol Levels During Acute Illnesses in Children and Adolescents: A Systematic Review","volume":"5","author":"Rezai","year":"2022","journal-title":"JAMA Netw. Open"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"729","DOI":"10.1080\/07435809609043769","article-title":"Activity of the adrenal fetal zone in preterm infants continues to term","volume":"22","author":"Midgley","year":"1996","journal-title":"Endocr Res"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/2\/235\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:01:22Z","timestamp":1760104882000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/14\/2\/235"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,17]]},"references-count":45,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["biom14020235"],"URL":"https:\/\/doi.org\/10.3390\/biom14020235","relation":{},"ISSN":["2218-273X"],"issn-type":[{"type":"electronic","value":"2218-273X"}],"subject":[],"published":{"date-parts":[[2024,2,17]]}}}