Psycho-Neurological and Immunological Aspects of Cushing’s Syndrome

Since the first description of the Cushing’s syndromeCushing’s syndrome (CS), many advances in the diagnosisDiagnosis and management of this condition have been achieved. However, there are still many difficulties in the management of patients with CS, particularly in the domains of psycho-neurology and immunology. Psycho-neurological manifestations are common in patients with CS and may be found throughout the whole spectrum of CS, both in the active and in the remission phases. These include psychiatric disorders, ranging from major depression, to anxietyAnxiety or mania, as well as neurocognitive disorders, including concentration and memory impairment. Additionally, chronic hypercortisolism in CS leads to structural and functional changes in the brain, particularly in the prefrontal cortex and limbic system. Such changes in the central nervous systemCentral nervous system improve after CS remission, but may not be fully reversible, explaining why some of the psycho-neurological manifestations may persist, or even worsen, after successful treatmentTreatment of CS. Hence, patients typically experience a significant impairment in the quality of lifeQuality of life during the active phase of CS, which may persist shortly after the treatmentTreatment of CS or even during the long-term remission. Low-degree inflammatory status, immune system dysfunction and immunosuppression related with the hypercortisolism are characteristic of patients with CS, owing to the effects of excessive levels of cortisolCortisol in the systemic inflammation and in the immune system. During the active phase of CS, patients experience inflammatory and immune-related problems, such as predisposition for severe infections, cardiometabolic abnormalities and venous thrombosis. Hypercortisolism induces changes in the innate and adaptive immunity, with some classical laboratorial readouts, such as leukocytosis and neutrophilia or lymphopenia. The activity of several immune cells may be compromised in CS, such as macrophagesMacrophage, natural killer (NK) cells, T lymphocytes, and there are increased levels of circulating pro-inflammatory cytokines. After remission, patients still continue to experience problems related with persistent low-grade inflammation or immune malfunction. The role of the microenvironment and of the immune system in the tumorigenic mechanisms, including in tumor proliferation and invasion, but also in hormoneHormone secretion, has been emerging over recent years. ACTH-secreting pituitary tumors, as well as cortisolCortisol-secreting adrenal tumors, are infiltrated by immune cells, and express immune-related proteins, such as PD-L1, which may render such tumors amenable for immunotherapy (e.g., immune checkpoint inhibitors). Thus, increasing knowledge in these domains may allow novel therapies for patients with CS, particularly to those with aggressive and/or refractory tumors. The management of psycho-neurological and immune-related issues in patients with CS should be part of the standard medical care in this setting. Recognizing and addressing such psycho-neurological and immune-related complications, before and after the treatmentTreatment of CS, will ultimately lead to an improvement in the quality of lifeQuality of life and in the clinical outcomes of patients with CS.