title: Gender-specific differences in hypothalamus-pituitary-adrenal axis activity during childhood: a systematic review and meta-analysis.
abstract: Gender-specific differences in hypothalamus-pituitary-adrenal (HPA) axis activity have been postulated to emerge during puberty. We conducted a systematic review and meta-analysis to test the hypothesis that gender-specific differences in HPA axis activity are already present in childhood.
  
  
  
  From inception to January 2016, PubMed and EMBASE.com were searched for studies that assessed non-stimulated cortisol in serum or saliva or cortisol in 24-h urine in healthy males and females aged ≤18 years. Studies that conform with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement were reported. Standardized mean differences (95% CIs) were calculated and analyzed using fixed-effect meta-analysis stratified for age: <8 years (prepubertal) and 8-18 years (peri-/postpubertal). For comparison, we ran the same analyses using random-effects models.
  
  
  
  Two independent assessors selected 413 out of 6158 records (7%) for full-text screening, of which 79 articles were included. Of these, 58 (with data on 16,551 subjects) were included in the meta-analysis. Gender differences in cortisol metabolism differed per age group. Boys aged <8 years had 0.18 (0.06; 0.30) nmol/L higher serum and 0.21 (0.05; 0.37) nmol/L higher salivary cortisol levels, while between 8 and 18 years, boys had 0.34 (0.28; 0.40) nmol/L lower serum and 0.42 (0.38; 0.47) nmol/L lower salivary cortisol levels. In 24-h urine, cortisol was consistently higher in boys, being 0.34 (0.05; 0.64) and 0.32 (0.17; 0.47) μg/24 h higher in the <8- and 8-18-year groups, respectively. However, gender-differences in serum cortisol <8 years and between 8 and 18 years were absent when using random-effects models.
  
  
  
  Gender differences in cortisol metabolism are already present in childhood, with higher salivary cortisol in boys aged <8 years compared to girls. This pattern was reversed after the age of 8 years. In contrast, the gender-specific difference in cortisol production as assessed through 24-h urine did not change with age. Although differences were small, and analyses of gender differences in serum cortisol were inconclusive, they might contribute to gender-specific origins of health and disease.
authors.affiliation: Department of Pediatric Endocrinology, VU University Medical Center, Postbus 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Bibian
authors.identifier: 0000-0003-1299-0067
authors.initials: B
authors.lastname: van der Voorn
authors.affiliation: Department of Pediatric Endocrinology, VU University Medical Center, Postbus 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Jonneke J
authors.initials: JJ
authors.lastname: Hollanders
authors.affiliation: Medical Library, Vrije Universiteit, De Boelelaan 1103, 1081 HV Amsterdam, The Netherlands.
authors.forename: Johannes C F
authors.initials: JCF
authors.lastname: Ket
authors.affiliation: Department of Pediatric Endocrinology, VU University Medical Center, Postbus 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Joost
authors.initials: J
authors.lastname: Rotteveel
authors.affiliation: Department of Pediatric Endocrinology, VU University Medical Center, Postbus 7057, 1007 MB Amsterdam, The Netherlands.
authors.forename: Martijn J J
authors.initials: MJJ
authors.lastname: Finken
mesh_terms: D002648:Child; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000502:physiology*; D010913:Pituitary-Adrenal System / Q000502:physiology*; D012727:Sex Characteristics
keywords: Glucocorticoid; Infant; Pediatric; Sex characteristics; Stress hormone