The Deleterious Effects of Glucocorticoids: From epidemiology to molecular perspective

Background: Cushing’s syndrome (CS) is caused by prolonged and inappropriately excessive tissue exposure to glucocorticoids (GC) [1]. CS results in significant morbidity and excess mortality. Increased 11β-hydroxysteroid dehydrogenase type1 (11β-HSD1) activity at local tissue has been documented for adverse cortisol effects. Aim: To explore the deleterious effects of systemic and local GC excess in man at molecular and epidemiological levels, which focuses on the outcomes that enable the quantification of disease burden and further avoidable premature death or morbidity. Methods: The epidemiological studies focused on a meta-analysis of mortality and causes of death in endogenous and exogenous CS. Mortality is a crucial health problem, and meta-analyses systematically explore the issue. The molecular study investigates 11β-HSD1 expression in hypoxia in human dermal fibroblasts. This is the preliminary research of 11β-HSD1 role in ischaemic/diabetic wounds, the worldwide health burden. The understanding of 11β-HSD1 in hypoxic skin may yield a new treatment for diabetic/ischaemic wounds. Results: The pooled proportion of death for endogenous CS was 5%, 4% in Cushing's disease (CD), 2% in adrenal adenoma, but 8% in bilateral adrenal hyperplasia. The standardised mortality ratio (SMR) was 3.0 for all CS. ACS was associated with a worse SMR than CD (p=0.003). Mortality was higher in publications published before 2000, active disease, and macroadenomas. Cumulative, average, and initial GC doses are associated with increased mortality in exogenous CS. Cardiovascular diseases, infection and malignancy, are the major contributors to deaths for all CS. Hypoxia increases 11β-HSD1 expression and activity in HDF, particularly in inflammatory conditions for the molecular study. Conclusion: CS confirmed the association with an increase in mortality. The causes of death highlight the need for aggressive management. The 11β-HSD1 role in hypoxia requires further research in ischaemic or diabetic human skin with is the new hope for curing the wound