Hypothalamic-pituitary-adrenal axis dysfunction in children with ADHD: A systematic review and meta-analysis

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in children, characterized by persistent inattention, hyperactivity and impulsivity. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been proposed as one neurobiological mechanism, yet findings across individual studies are inconsistent.

To quantify differences in HPA-axis function between children under 18 years with ADHD and typically developing (TD) controls across multiple biological markers. TD children were defined as having no diagnosis of ADHD or any other psychiatric or neurodevelopmental disorder.

A systematic review and random-effects meta-analysis of studies published from 1999 to 2025 was performed following PRISMA guidelines. Searches of PubMed, Embase, Web of Science, SpringerLink, CNKI, Wanfang, VIP and CBM identified studies reporting adrenocorticotropic hormone (ACTH), basal cortisol (saliva or blood), cortisol awakening response (CAR), stress-reactive cortisol or hair cortisol concentration (HCC). Pooled effect sizes were expressed as standardized mean differences (SMDs) with 95 % confidence intervals (CIs). Heterogeneity was assessed with the I² statistic; publication bias was examined using funnel plots and Egger's test.

Thirty-four studies (n = 4635; 2559 ADHD, 2076 TD) met inclusion criteria. Compared with TD controls, children with ADHD had significantly lower morning awakening cortisol (SMD = -0.63, 95 % CI -0.93 to -0.34), 30-min post-awakening cortisol (SMD = -0.39, 95 % CI -0.54 to -0.23), afternoon cortisol (SMD = -0.85, 95 % CI -1.63 to -0.06) and post-test cortisol (SMD = -2.14, 95 % CI -3.93 to -0.34). No group differences emerged for ACTH, CAR, pre-test cortisol or HCC. Subgroup analyses showed larger effects in blood versus saliva matrices and in studies from China; the hypocortisolemic profile was most pronounced in the hyperactive-impulsive (ADHD-HI) subtype. Meta-regression identified no significant moderators, and no evidence of publication bias was detected.

ADHD may exhibit a consistent pattern of HPA-axis hypoactivity, affecting both basal secretion and stress responsiveness, whereas ACTH, CAR and HCC appear preserved. The effect is strongest in the ADHD-HI subtype and when cortisol is measured in blood, indicating a subtype-specific and matrix-dependent neuroendocrine phenotype. These findings may support HPA-axis dysregulation as a potential biological correlate of ADHD.