![]() (d) The ACTH 1–24 test, i.e., 250 μg of synthetic ACTH 1–24 is administered and, during the subsequent hours, multiple plasma cortisol samples are analyzed to quantify cortisol. (c) The CRF test, whereby multiple blood samples are extracted at different times to quantify ACTH and cortisol variations following the administration of 1 μg/kg of ovine CRF. Supersuppression occurs when the suppression is greater than that observed in healthy controls, while reduced suppression indicates a malfunction of the negative autoregulatory feedback loop. An abnormal suppression reaction, i.e., an excess (supersuppression) or reduced suppression, are signs of dysfunction of the HPA axis. That said, in normal circumstances, DXM suppresses ACTH and cortisol release. Therefore, a suppression of the HPA axis activity by the negative-feedback loop is expected upon its administration patients with MDD are known to show abnormal responses to DXM. DXM is a synthetic glucocorticoid whose mechanism of action resembles that of endogenous cortisol. (b) The dexamethasone (DXM) test, i.e., administering a dose of DXM (0.5 to 1.5 mg) at night (day 1) and measuring plasma cortisol the next morning (day 2). (a) basal cortisol and/or ACTH measurement in saliva usually during the early morning (upon awakening and minutes later) or hair cortisol/ACTH. The following were deployed by the different studies to measure the activity of the HPA axis. This could ultimately lead to: (a) hypoactivity of the HPA axis due to an adaptative enhancement of negative feedback on hypothalamic glucocorticoid receptors by cortisol, which could mirror biological malfunctions typically found in PTSD (b) desensitization of CRF pituitary receptors caused by excessive CRF secretion, that could lead to a perpetuation of a high CRF concentration in the central nervous system (CNS) and (c) diminution of the number of or the desensitization of hypothalamic glucocorticoid receptors that results in an inhibition of the negative-feedback loop, and consequently permanent hyperactivity of the axis (elevated ACTH/cortisol secretion). It has been postulated that ELS induces hypersecretion of corticotropin-release factor (CRF) by the hypothalamus that results in a hyperactivity of the HPA axis and its consequent elevated cortisol release. Curiously, the co-occurrence of MDD and PTSD and a symptoms overlap is appreciable. MDD has been traditionally associated with hyperactivity of the HPA axis, while posttraumatic stress disorder (PTSD), another related psychopathology, has been linked to a hypoactivity of the same axis. It is well known that stress triggers multiple physiological responses, perhaps the most representative being the activation of the hypothalamic-pituitary-adrenal (HPA) axis and its consequent release of adrenocorticotropic hormone (ACTH) and cortisol. Future studies are needed to clarify the exact mechanisms involved. ![]() Conclusion: HPA dysfunction found in MDD seems to be more related to the presence of ELS rather than to the MDD itself. Dysfunction of the HPA axis was also found in the no-MDD/ELS groups. A greater number of abnormalities and a higher rate of posttraumatic stress disorder comorbidity were found in the MDD/ELS group. Results: Hyperactivity or hypoactivity of the HPA axis was found in 8 articles. 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. Original articles were found in PubMed and via a manual search. Methods: The review was conducted by following the PRISMA guidelines. 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. 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. Nevertheless, these alterations are not found in every patient. Background: Alterations of the hypothalamic-pituitary-adrenal (HPA) axis are common in patients diagnosed with major depressive disorder (MDD).
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