Psychological and Physiological Stress and the Onset and Course of Graves' Disease: A Systematic Review.

Graves' disease (GD) is the most common cause of autoimmune hyperthyroidism, and stress has long been implicated in its onset. Whether stress genuinely triggers thyroid autoimmunity or is an epiphenomenon of evolving hyperthyroidism remains unclear. This systematic review appraised original observational studies examining the association between psychological and physiological stress and the onset and clinical course of GD. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement, MEDLINE/PubMed, Embase, Scopus, Web of Science, PsycINFO and the Cochrane Library were searched from database inception to June 19, 2026. Eligible studies were original case-control or cohort investigations assessing stress exposure with validated instruments in patients with confirmed GD relative to a control or comparison group. Reviews, case reports, conference abstracts, and preprints were excluded. Methodological quality was appraised with the Newcastle-Ottawa Scale (NOS), a validated nine-point instrument for non-randomized studies rating selection, comparability, and exposure or outcome ascertainment, with predefined thresholds used to classify risk of bias. Certainty of evidence was rated using Grading of Recommendations Assessment, Development and Evaluation (GRADE). Substantial heterogeneity in exposure instruments, comparators, and outcome metrics precluded meta-analysis, so the evidence was synthesized narratively. Thirteen studies, enrolling at least 2,867 participants and including 1,134 patients with confirmed GD, met the eligibility criteria. Most retrospective case-control studies reported a significantly higher burden of negative life events in the 12 months preceding GD diagnosis than in controls, with large effect estimates and a female-predominant association. Where patients with non-autoimmune toxic nodular goitre served as comparators, the excess was confined to the autoimmune group. Three studies linked stress to disease recurrence and to a poorer response to antithyroid drug therapy, again chiefly in women. Conversely, the prospective cohort and a chronic endogenous stress study found no association with de novo thyroid autoimmunity or incident GD. Overall certainty of evidence was very low, principally because of the predominantly retrospective designs with attendant recall bias and reverse causation, inconsistency between retrospective and prospective findings, and imprecision from small samples. Retrospective evidence supports an association between antecedent stress and GD onset and, to a lesser extent, its course in genetically predisposed individuals, particularly women, while the limited prospective evidence is inconsistent with this association. Adequately powered prospective cohort studies employing standardised stress instruments and objective stress biomarkers are needed before a causal role can be affirmed.