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

Area of Science:

• Neuroendocrinology
• Child Psychology
• Developmental Neuroscience

Background:

• Attention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder in children.
• HPA axis dysregulation is a proposed, yet inconsistently reported, neurobiological mechanism in ADHD.

Purpose of the Study:

• To systematically evaluate and quantify differences in HPA axis function between children with ADHD and typically developing (TD) controls.
• To investigate multiple biological markers of HPA axis activity.

Main Methods:

• A systematic review and random-effects meta-analysis of studies published between 1999 and 2025.
• Searches included major databases (PubMed, Embase, etc.) for studies measuring ACTH, cortisol (basal, CAR, stress-reactive, hair), following PRISMA guidelines.
• Pooled effect sizes (SMDs) and confidence intervals were calculated; heterogeneity and publication bias were assessed.

Main Results:

• Thirty-four studies including 4635 children were analyzed.
• Children with ADHD exhibited significantly lower morning awakening cortisol, 30-min post-awakening cortisol, afternoon cortisol, and post-test cortisol compared to TD controls.
• No significant group differences were found for ACTH, CAR, pre-test cortisol, or hair cortisol concentration (HCC).

Conclusions:

• ADHD is associated with a consistent pattern of HPA axis hypoactivity, impacting basal secretion and stress response.
• This hypoactive profile is most evident in the hyperactive-impulsive (ADHD-HI) subtype and when cortisol is measured in blood.
• Findings suggest HPA axis dysregulation as a potential biological correlate of ADHD, with subtype-specific neuroendocrine characteristics.