SYSTEMATIC REVIEW AND META-ANALYSIS ON THE CORTISOL LEVELS IN PRIMARY HEADACHE DISORDERS: A POSSIBLE BIOMARKER OR THERAPEUTIC APPROACH?

Primary headaches are highly prevalent neurological conditions classified as migraine, tension-type headache, and cluster headache. These neurovascular disorders involve pathophysiological mechanisms that remain not fully elucidated, hindering the development of effective treatments. Evidence suggests that chronic stress and dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis, particularly through cortisol release, may contribute to the onset and maintenance of headache episodes. This study aims to conduct a systematic review and meta-analysis of cortisol levels in patients with primary headaches.
The protocol was registered in PROSPERO (CRD420250647831) and reported following the PRISMA 2020 checklist. Quality and risk of bias of included studies were assessed using the Newcastle-Ottawa Scale (NOS), and publication bias was evaluated using Egger’s and Begg’s tests. Through searches in PubMed, Scopus, Web of Science, and the Cochrane Library in March 2025, 10,856 records were identified. After screening and eligibility assessment, 14 studies were included in the systematic review, comprising a total of 393 headache patients (226 females, 167 males) and 294 healthy controls.
Meta-analysis results showed that cortisol levels are elevated in chronic migraine and cluster headache during active phases and remission compared with controls. Increased cortisol concentrations were observed in serum, blood, and saliva samples, with elevations present across morning, afternoon, and night assessments. These findings indicate that dysregulation of cortisol may play a role in the pathophysiology of primary headaches and could represent both a therapeutic target and a research direction. Cortisol may function as a biomarker of disease activity or transition from episodic to chronic migraine.