The Relationship between COVID-19 and Hypothalamic–Pituitary–Adrenal Axis: A Large Spectrum from Glucocorticoid Insufficiency to Excess—The CAPISCO International Expert Panel

Abstract

Coronavirus disease 2019 (COVID-19) is a highly heterogeneous disease regarding severity, vulnerability to infection due to comorbidities, and treatment approaches. The hypothalamic–pituitary–adrenal (HPA) axis has been identified as one of the most critical endocrine targets of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that might significantly impact outcomes after infection. Herein we review the rationale for glucocorticoid use in the setting of COVID-19 and emphasize the need to have a low index of suspicion for glucocorticoid-induced adrenal insufficiency, adjusting for the glucocorticoid formulation used, dose, treatment duration, and underlying health problems. We also address several additional mechanisms that may cause HPA axis dysfunction, including critical illness-related corticosteroid insufficiency, the direct cytopathic impacts of SARS-CoV-2 infection on the adrenals, pituitary, and hypothalamus, immune-mediated inflammations, small vessel vasculitis, microthrombotic events, the resistance of cortisol receptors, and impaired post-receptor signaling, as well as the dissociation of ACTH and cortisol regulation. We also discuss the increased risk of infection and more severe illness in COVID-19 patients with pre-existing disorders of the HPA axis, from insufficiency to excess. These insights into the complex regulation of the HPA axis reveal how well the body performs in its adaptive survival mechanism during a severe infection, such as SARS-CoV-2, and how many parameters might disbalance the outcomes of this adaptation.

Is SARS-CoV-2 a Risk Factor of Bipolar Disorder?—A Narrative Review

“…In the context of COVID-19, there are also cases of newly diagnosed adrenal insufficiency (AI) confirmed by the adrenocorticotropic hormone (ACTH) stimulation test, and their incidence, depending on the study, reaches up to 64% [ 114 , 115 , 116 ]. Critical illness-related corticosteroid insufficiency (CIRCI) is a known phenomenon, and its occurrence is associated with a decrease in cortisol transport and a reduction in its breakdown, insufficient GR-α activity, inhibition of ACTH secretion and steroidogenesis [ 117 , 118 ]. In the case of COVID-19, the AI hypotheses include (1) direct effect of SARS-CoV-2 virus on the pituitary and hypothalamus, which express angiotensin-converting enzyme 2 (ACE2) receptors (2) direct effect on the adrenal glands (3) similarity of the viral amino acid sequence to the ACTH amino acid sequence and immune cross-reaction (4) reduction in ACTH release induced by TNF-α (5) dysfunction of the HPA axis caused by cytokine storm (6) critical condition and the resulting CIRCI (7) reduction in adrenal venous drainage by artery dilating effect of ACTH (8) effect of exogenous corticosteroids [ 116 , 118 , 119 ].…”

“…In summary, infection with SARS-CoV-2 leads to disturbances in the HPA axis but the direction of those disturbances is not consistent across studies—same as for BD [ 109 , 110 , 112 ]. In relation to COVID-19, a large proportion of research on the HPA axis reports hypercortisolemia, but there are also references to hypocortisolemia and AI [ 116 , 118 , 119 ]. High cortisol levels in COVID-19 patients could possibly be associated with its subsequent decline and large diurnal fluctuations in its level, which could cause manic symptoms [ 106 ].…”

The Dual Pandemics of COVID-19 and Obesity: Bidirectional Impact

“…There is a bidirectional impact of obesity and COVID-19 on each other, and we have emphasized the importance of a novel multidisciplinary syndemic approach for better management of subjects with obesity during the COVID era [ 84 , 85 ]. In this review we provide a comprehensive review on the recent evidence that supports the impact of obesity on COVID-19 outcomes.…”

Glucocorticoids and COVID-19

“…An important issue about the heterogeneity of the GC response is whether variations in the endogenous GC-GR interaction (or in the HPA axis) can contribute to the response in COVID-19 patients. Some authors suggest that COVID-19 patients with pre-existing HPA axis dysfunction should still be considered potentially vulnerable groups [157] , [158] , [159] . Also, patients with adrenocortical carcinoma could be more susceptible to SARS-CoV-2 infection due to the immunosuppressive state caused by unbalanced GC secretion [160] .…”