Long-term glucocorticoids in relation to the metabolic syndrome and cardiovascular disease: A systematic review and meta-analysis

The striking link of Cushing's syndrome with the metabolic syndrome (MetS) and cardiovascular disease (CVD) suggests that long-term exposure to extremely high cortisol levels catalyzes cardiometabolic deterioration. However, it remained unclear whether the findings from the extreme glucocorticoid overabundance observed in Cushing's syndrome could be translated into more subtle variations in long-term glucocorticoid levels among the general population, for example, due to chronic stress. Here, we performed a systematic review (PROSPERO: CRD42023425541) of evidence regarding the role of subtle variations in long-term biological stress, measured as levels of scalp hair cortisol (HairF) and cortisone (HairE), in the context of MetS and CVD in adults. We also performed a meta-analysis on the cross-sectional difference in HairF levels between individuals with versus without CVD. Seven studies were included regarding MetS, sixteen regarding CVD, and one regarding both. Most articles indicated a strong, consistent cross-sectional association of higher HairF and HairE levels with CVD, which was confirmed by our meta-analysis for HairF (eight studies, SMD = 0.48, 95% confidence intervals [CIs]: 0.16–0.79, p = 0.0095). Moreover, these relationships appear largely independent of standard risk factors. Age seems relevant as the effect seems stronger in younger individuals. Results regarding the associations of HairF and HairE with MetS were inconsistent. Altogether, long-term biological stress, measured as HairF and HairE, is associated with the presence of CVD, and less consistently with MetS. Prospective studies need to evaluate the directionality of this relationship and determine whether HairF and HairE can be used in addition to standard risk factors in predicting future cardiometabolic deterioration.