{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T16:45:16Z","timestamp":1777481116413,"version":"3.51.4"},"reference-count":33,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2019,4,26]],"date-time":"2019-04-26T00:00:00Z","timestamp":1556236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>The consumption of high levels of dietary caffeine has increased in children and adolescents. Human and animal studies have shown that chronic intake of high doses of caffeine affects serum glucocorticoid levels. Given that glucocorticoids play a role in peripubertal organ growth and development, chronic high doses of caffeine during puberty might impair maturation of the adrenal glands. To evaluate any effects of caffeine exposure on growing adrenal glands, 22-day-old male (n = 30) and female Sprague Dawley rats (n = 30) were divided into three groups (n = 10\/group); group 1 received tap water (control) and groups 2 and 3 received water containing 120 and 180 mg\/kg\/day caffeine, respectively, via gavage for 4 weeks. At the end of the experiment, adrenal glands were weighed and processed for histological analysis. Relative adrenal weights increased in both groups of caffeine-fed males and females, whereas absolute weights were decreased in the females. In the female caffeine-fed groups the adrenal cortical areas resembled irregularly arranged cords and the medullary area was significantly increased, whereas no such effects were seen in the male rats. Our results indicate that the harmful effects of caffeine on the adrenal glands of immature rats differ between females and males. Although female rats seemed to be more susceptible to damage based on the changes in the microarchitecture of the adrenal glands, caffeine affected corticosterone production in both female and male rats. In addition, increased basal adrenocorticotropic hormone levels in caffeine-fed groups may reflect decreased cortical function. Therefore, caffeine may induce an endocrine imbalance that disturbs the establishment of the hypothalamo\u2013pituitary adrenal axis during puberty, thereby leading to abnormal stress responses.<\/jats:p>","DOI":"10.3390\/nu11050951","type":"journal-article","created":{"date-parts":[[2019,4,26]],"date-time":"2019-04-26T07:52:59Z","timestamp":1556265179000},"page":"951","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["The Effects of High Peripubertal Caffeine Exposure on the Adrenal Gland in Immature Male and Female Rats"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7094-300X","authenticated-orcid":false,"given":"Ki-Young","family":"Ryu","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, College of Medicine, Hanyang University, Seoul 133-791, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6286-1071","authenticated-orcid":false,"given":"Jaesook","family":"Roh","sequence":"additional","affiliation":[{"name":"Dept. of Anatomy and Cell Biology, College of Medicine, Hanyang University, Seoul 133-791, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.drugalcdep.2008.08.001","article-title":"Caffeinated energy drinks\u2014A growing problem","volume":"99","author":"Reissig","year":"2009","journal-title":"Drug Alcohol Depend."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1542\/peds.2009-3592","article-title":"Health effects of energy drinks on children, adolescents, and young adults","volume":"127","author":"Seifert","year":"2011","journal-title":"Pediatrics"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"557","DOI":"10.3109\/15563650.2013.820311","article-title":"Behavioral and physiologic adverse effects in adolescent and young adult emergency department patients reporting use of energy drinks and caffeine","volume":"51","author":"Jackson","year":"2013","journal-title":"Clin. Toxicol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1080\/10520295.2018.1499961","article-title":"Chronic stress and high sucrose intake cause distinctive morphometric effects in the adrenal glands of post-weaned rats","volume":"93","year":"2018","journal-title":"Biotech. Histochem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/0272-0590(84)90224-0","article-title":"The effects of drugs and chemicals upon the structure of the adrenal gland","volume":"4","author":"Ribelin","year":"1984","journal-title":"Fundam. Appl. Toxicol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1016\/j.psyneuen.2016.01.030","article-title":"Adolescent caffeine consumption increases adulthood anxiety-related behavior and modifies neuroendocrine signaling","volume":"67","author":"Newsom","year":"2016","journal-title":"Psychoneuroendocrinology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1172\/JCI110124","article-title":"Tolerance to the humoral and hemodynamic effects of caffeine in man","volume":"67","author":"Robertson","year":"1981","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.taap.2015.03.028","article-title":"Increased DNA methylation of scavenger receptor class B type I contributes to inhibitory effects of prenatal caffeine ingestion on cholesterol uptake and steroidogenesis in fetal adrenals","volume":"285","author":"Wu","year":"2015","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1039\/C5TX00265F","article-title":"Prenatal caffeine exposure-induced adrenal developmental abnormality in male offspring rats and its possible intrauterine programming mechanisms","volume":"5","author":"He","year":"2016","journal-title":"Toxicol. Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Xu, D., Zhang, B., Liang, G., Ping, J., Kou, H., Li, X., Xiong, J., Hu, D., Chen, L., and Magdalou, J. (2012). Caffeine-induced activated glucocorticoid metabolism in the hippocampus causes hypothalamic-pituitary-adrenal axis inhibition in fetal rats. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0044497"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1016\/j.ecl.2015.02.001","article-title":"Development of adrenal cortex zonation","volume":"44","author":"Xing","year":"2015","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1210\/endo-119-4-1816","article-title":"Increased pituitary sensitivity to glucocorticoid feedback during the stress nonresponsive period in the neonatal rat","volume":"119","author":"Walker","year":"1986","journal-title":"Endocrinology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1016\/j.ntt.2008.02.002","article-title":"Increased emotional reactivity in rats following exposure to caffeine during adolescence","volume":"30","author":"Anderson","year":"2008","journal-title":"Neurotoxicol. Teratol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1159\/000122169","article-title":"Postweaning development of negative feedback in the pituitary-adrenal system of the rat","volume":"12","author":"Goldman","year":"1973","journal-title":"Neuroendocrinology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"476","DOI":"10.1080\/10253890.2017.1369523","article-title":"Hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes: Sex differences in regulation of stress responsivity","volume":"20","author":"Oyola","year":"2017","journal-title":"Stress"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"368475","DOI":"10.1155\/2015\/368475","article-title":"High doses of caffeine during the peripubertal period in the rat impair the growth and function of the testis","volume":"2015","author":"Park","year":"2015","journal-title":"Int. J. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1016\/j.reprotox.2017.01.007","article-title":"Peri-pubertal high caffeine exposure increases ovarian estradiol production in immature rats","volume":"69","author":"Kwak","year":"2017","journal-title":"Reprod. Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1046\/j.1365-3016.2003.00507.x","article-title":"High caffeine consumption in the third trimester of pregnancy: Gender-specific effects on fetal growth","volume":"17","author":"Vik","year":"2003","journal-title":"Paediatr. Perinat. Epidemiol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Ojeda, S.R., and Skinner, M.K. (2006). Puberty in the rat. Knobil and Neill\u2019s Physiology of Reproduction, Elsevier.","DOI":"10.1016\/B978-012515400-0\/50043-9"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1016\/S8756-3282(01)00659-7","article-title":"Effects of caffeine and exercise on the development of bone: A densitometric and histomorphometric study in young Wistar rats","volume":"30","author":"Huang","year":"2002","journal-title":"Bone"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/oby.2002.8","article-title":"Association of lean tissue and fat mass with bone mineral content in children and adolescents","volume":"10","author":"Pietrobelli","year":"2002","journal-title":"Obes. Res."},{"key":"ref_22","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_23","first-page":"378","article-title":"Developmental and functional biology of the primate fetal adrenal cortex","volume":"18","author":"Mesiano","year":"1997","journal-title":"Endocr. Rev."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1093\/clinchem\/4.6.462","article-title":"An enzymatic method for glucose determination in body fluids","volume":"4","author":"Beach","year":"1958","journal-title":"Clin. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e7","DOI":"10.3928\/19382359-20171214-04","article-title":"Premature adrenarche","volume":"47","author":"Novello","year":"2018","journal-title":"Pediatr. Ann."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1016\/0040-8166(92)90019-4","article-title":"Age-related changes in the morphology and function of the zona glomerulosa of the rat adrenal cortex","volume":"24","author":"Belloni","year":"1992","journal-title":"Tissue Cell"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1080\/01926230490465874","article-title":"Relationships between organ weight and body\/brain weight in the rat: What is the best analytical endpoint?","volume":"32","author":"Bailey","year":"2004","journal-title":"Toxicol. Pathol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1007\/BF00213800","article-title":"Sex differences in adrenocortical structure and function. XII. Stereologic studies of rat adrenal cortex in the course of maturation","volume":"232","author":"Majchrzak","year":"1983","journal-title":"Cell Tissue Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1080\/019262301301418847","article-title":"Adrenal gland: Structure, function, and mechanisms of toxicity","volume":"29","author":"Rosol","year":"2001","journal-title":"Toxicol. Pathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1016\/j.pbb.2006.07.012","article-title":"HPA function in adolescence: Role of sex hormones in its regulation and the enduring consequences of exposure to stressors","volume":"86","author":"McCormick","year":"2007","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1016\/j.taap.2018.01.008","article-title":"IGF1\/MAPK\/ERK signaling pathway-mediated programming alterations of adrenal cortex cell proliferation by prenatal caffeine exposure in male offspring rats","volume":"341","author":"Chen","year":"2018","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/S1043-6618(05)80005-2","article-title":"Metabolic and hormone-related responses to caffeine in rats","volume":"32","author":"Leblanc","year":"1995","journal-title":"Pharmacol. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.psyneuen.2005.11.008","article-title":"Modulation of the hypothalamo-pituitary-adrenocortical axis by caffeine","volume":"31","author":"Patz","year":"2006","journal-title":"Psychoneuroendocrinology"}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/5\/951\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:47:24Z","timestamp":1760186844000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/11\/5\/951"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,26]]},"references-count":33,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2019,5]]}},"alternative-id":["nu11050951"],"URL":"https:\/\/doi.org\/10.3390\/nu11050951","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,26]]}}}