Development of 24-Hour Rhythms in Cortisol Secretion Across Infancy: A Systematic Review and Meta-Analysis of Individual Participant Data.

Stefan A Wudy, Melissa W Clearfield, Rima Azar, Rina D Eiden, Lauren E Philbrook, Marieke S Tollenaar, Britney S J Chen, Kirsten N G van de Weijer, Andries Kalsbeek, Carolina de Weerth, Yang Cao, Roseriet Beijers, George L Burchell, Nicole R Bush, Martijn J J Finken, Joost Rotteveel, Evalotte Mörelius, Grazyna Kmita, Michael Gröschl, Marcela Tamayo-Ortiz, Laura Kervezee, Michelle Romijn, Adina Chis

Journal: The Journal of clinical endocrinology and metabolism 2025;110(2):e515-e524

PMID: 39207206

Abstract

CONTEXT

In adults, cortisol levels show a pronounced 24-hour rhythm with a peak in the early morning. It is unknown at what age this early-morning peak in cortisol emerges during infancy, hampering the establishment of optimal dosing regimens for hydrocortisone replacement therapy in infants with an inborn form of adrenal insufficiency.

OBJECTIVE

We aimed to characterize daily variation in salivary cortisol concentration across the first year of life.

METHODS

We conducted a systematic review followed by an individual participant data meta-analysis of studies reporting on spontaneous (ie, not stress-induced) salivary cortisol concentrations in healthy infants aged 0-1 year. A one-stage approach using linear mixed-effects modeling was used to determine the interaction between age and time of day on cortisol concentrations.

RESULTS

Through the systematic review, 54 eligible publications were identified, reporting on 29 177 cortisol observations. Individual participant data were obtained from 15 study cohorts, combining 17 079 cortisol measurements from 1904 infants. The morning/evening cortisol ratio increased significantly from 1.7 (95% CI: 1.3-2.1) at birth to 3.7 (95% CI: 3.0-4.5) at 6 to 9 months (P < .0001). Cosinor analysis using all available data revealed the gradual emergence of a 24-hour rhythm during infancy.

CONCLUSION

The early-morning peak in cortisol secretion gradually emerges from birth onwards to form a stable morning/evening ratio from age 6 to 9 months. This might have implications for hydrocortisone replacement therapy in infants with an inborn form of adrenal insufficiency.

© The Author(s) 2024. Published by Oxford University Press on behalf of the Endocrine Society.

Address: Group of Circadian Medicine, Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands.; Department of Pediatric Endocrinology, Emma Children's Hospital, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands.; Amsterdam Reproduction & Development Research Institute, 1105 AZ Amsterdam, The Netherlands.; Department of Pediatric Endocrinology, Emma Children's Hospital, Amsterdam UMC, 1105 AZ Amsterdam, The Netherlands.; Medical Library, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands.; Department of Clinical Psychology, Institute of Psychology, Leiden University, 2333 AK Leiden, The Netherlands.; Department of Environmental Health Sciences, Columbia Center for Children's Environmental Health, Columbia University Mailman School of Public Health, New York, NY 10032, USA.; Department of Psychological and Brain Sciences, Colgate University, Hamilton, NY 13346, USA.; Department of Human Development and Family Studies, The Pennsylvania State University, University Park, PA 16802, USA.; Radboud University Medical Centre, Donders Institute for Brain, Cognition and Behaviour, 6525 EN Nijmegen, The Netherlands.; Clinical Epidemiology and Biostatistics, Department of Medical Sciences, Faculty of Medicine and Health, Örebro University, Örebro 70185, Sweden.; Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm 17177, Sweden.; Unit of Integrative Epidemiology, Institute of Environmental Medicine, Karolinska Institute, Stockholm 17177, Sweden.; Department of Psychology and the Social Science Research Institute, The Pennsylvania State University, University Park, PA 16801, USA.; Psychobiology of Stress & Health Lab, Psychology Department, Mount Allison University, New Brunswick, E4L 1C7, Canada.; Departments of Psychiatry and Pediatrics, University of California, San Francisco (UCSF), San Francisco, CA 94158, USA.; Department of Molecular Sciences, "Iuliu Hațieganu" University of Medicine and Pharmacy, 400349 Cluj-Napoca, Romania.; Cognitive Neuroscience Laboratory, Babes-Bolyai University, 400294 Cluj-Napoca, Romania.; Department of Clinical Psychology of Child and Family, Faculty of Psychology, University of Warsaw, 00-183 Warsaw, Poland.; Department of Early Psychological Intervention, Institute of Mother and Child, 01-211 Warsaw, Poland.; Department of Psychology, Whitman College, Walla Walla, WA 99362, USA.; Department of Developmental Psychology, Behavioral Science Institute, Radboud University, 6500 HB Nijmegen, The Netherlands.; Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, 6500 HB Nijmegen, The Netherlands.; Celerion Switzerland AG, 8320 Fehraltorf, Switzerland.; Paediatric Endocrinology & Diabetology, Center of Child and Adolescent Medicine, Justus Liebig University, D-35392 Giessen, Germany.; Department of Endocrinology and Metabolism, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.; Netherlands Institute for Neuroscience (NIN), an Institute of the Royal Netherlands Academy of Arts and Sciences (KNAW), 1105 BA Amsterdam, The Netherlands.; Laboratory of Endocrinology, Department of Laboratory Medicine, Amsterdam UMC, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.; Amsterdam Gastroenterology Endocrinology Metabolism, Endocrinology, Metabolism and Nutrition, 1105 AZ Amsterdam, The Netherlands.; Amsterdam Neuroscience, Cellular and Molecular Mechanisms, 1105 AZ Amsterdam, The Netherlands.; Department of Health, Medicine and Caring Sciences, Linköping University, 58185 Linköping, Sweden.; School of Nursing and Midwifery, Edith Cowan University, Joondalup, WA 6027, Australia.
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