Context: Glucocorticoids (GC) mediate some of the adverse health-related consequences of circadian misalignment, such occurs in shift workers who have an increased cardio-metabolic, immune and cancer risk. Investigating the effect of circadian cortisol exposure in patients with GC excess and defect is crucial. In a therapeutic perspective large attention has been given to the total daily GC exposure, much less to the timing-of-the-day relative exposure. Clock genes are essential components of the machinery controlling circadian functions and are synchronized by GCs. Until recently, clock genes have not been investigated in patients with Adrenal Insufficiency (AI) or Cushings syndrome (CS), despite they represent a disease model of endogenous clock misalignment.
Objective: We evaluated the effect of the timing of GC exposure on circadian gene expression in peripheral blood mononuclear cells (PBMCs) of patients with AI or CS enrolled in the DREAM1 and TheHOURS (The circadian rhythm in cusHing syndrOme in active phase and dUring RemiSsion) trials.
Results: Compared with healthy controls, we found dysregulated many clock-related genes, with a distinctive profile in the AI and CS groups. Several metabolic and inflammatory signalling pathways were found altered in patients exposed to high evening/night GC levels or multiple peaks and trough during the day. Disease-specific effects were found in the profile of circulating PBMCs. More, PBMCs fluctuations during the day was not entirely abolished, but shifted or altered in patter and intensity. Medical interventions were partially able to restore the expression on clock-related genes, intracellular signalling and profiles of circulating PBMCs.
Conclusions: Pharmacological strategies designed to consider circadian timing of drug/hormone delivery, and circadian regulation of drug metabolism and of target gene/protein expression may be beneficial in the treatment of many chronic HPA-axis disorders.
Reference: 1. Isidori AM et al. Lancet Diabetes Endocrinol. 2018; 6(3):173 & Venneri MA et al. JCEM 2018; 103(8):2998.
18 - 21 May 2019
European Society of Endocrinology