Bibian van der Voorn

170 CHAPTER 11 exogenous (e.g., pharmacological, physical or social) or endogenous (e.g., cortisol awakening response (CAR)) stimuli. In addition, we included diurnal rhythm as a marker of the responsiveness of the HPA axis, although it functions differently from reactions of the HPA axis to stressors. We hypothesized that sex-specific HPA axis reactivity is already present early in life. METHODS SEARCH STRATEGY PubMed and Embase.com were searched from inception up to January 14 th , 2016 for studies addressing HPA axis reactivity in serum or saliva in boys and girls aged ≤18 years by reports of either absolute cortisol values, slopes, AUC’s and/ or through visualization of the data in figures. The full search strategy is detailed in Appendix 1, Chapter 9 and was based on the index terms or free-text words ‘cortisol’ or ‘glucocorticoid’, and ‘sex difference’ or ‘sexual characteristics’, and ‘child’ or ‘adolescent’. We excluded studies on children with (psycho)pathology, on synthetic glucocorticoids or with a risk of abnormal HPA axis reactivity (e.g., maltreatment). We did not impose restrictions on the year of publication or study design, apart from reviews and case reports, but we did apply an English language restriction. The review protocol was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement. DATA COLLECTION Two independent assessors (BvdV and JJH) screened 6,158 titles and abstracts for assessment of sex-specific HPA axis reactivity. Studies were not assessed blindly. Disagreement between assessors was discussed until consensus was reached. One- hundred and nine were eligible for full-text screening, of which 81 studies were included in the systematic review. Figure 1 shows the flowchart of the search. When reports of results were unclear, the authors were contacted (n=4); two authors responded. One author did not reply and one replied but could not provide sufficient data, resulting in exclusion of these studies. Additionally, articles were excluded when (1) no statistical analysis of reactivity was performed (n=9), (2) pharmacological stress tests did not use CRH and/ or ACTH (n=2), (3) HPA axis reactivity was presented stratified by gender, without analyzing gender differences (n=6), (4) gender was analyzed only as a confounder or