<b><i>Background:</i></b> Alterations of the hypothalamic-pituitary-adrenal (HPA) axis are common in patients diagnosed with major depressive disorder (MDD). Nevertheless, these alterations are not found in every patient. There is evidence to indicate a possible mediating role of early life stress (ELS) in the relation between dysfunction of the HPA axis and MDD. We conducted a systematic review to understand if the alterations of the HPA axis commonly found in patients with MDD are due to early life stress or are caused by the disorder itself. <b><i>Methods:</i></b> The review was conducted by following the PRISMA guidelines. Original articles were found in PubMed and via a manual search. Only studies whose design allowed comparison of the HPA functioning in the 4 groups no-MDD/no-ELS, MDD/no-ELS, no-MDD/ELS, and MDD/ELS were included. <b><i>Results:</i></b> Hyperactivity or hypoactivity of the HPA axis was found in 8 articles. A greater number of abnormalities and a higher rate of posttraumatic stress disorder comorbidity were found in the MDD/ELS group. Dysfunction of the HPA axis was also found in the no-MDD/ELS groups. <b><i>Conclusion:</i></b> HPA dysfunction found in MDD seems to be more related to the presence of ELS rather than to the MDD itself. Future studies are needed to clarify the exact mechanisms involved.

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