SUN-LB063 Peripheral Clock System Circadian Imbalance in Cushing's Disease

Context: Glucocorticoid circulating levels in healthy individuals oscillate according to a circadian rhythm, influenced by the molecular system of clock genes. In Cushing's syndrome, there is an altered cortisol daily rhythm, which can be associated to disruption of clock genes rhythmic expression. Objective: Evaluate the expression of clock genes (CLOCK, BMAL1, CRY1, CRY2, PER1, PER2, PER3) in leukocytes of healthy individuals and in patients with Cushing's disease (CD). Design and Participants: Case-control study with female Cushing’s disease patients (n=12) and controls (n=13). Main Outcome Measures: Participants underwent salivary cortisol measurement at 0900h and 2300h. Peripheral blood samples were obtained at 0900h, 1300h, 1700h and 2300h for assessing clock genes expression by qPCR. Gene expression profiles were evaluated by Cosinor analysis method. Results: In healthy controls, there was a circadian variation of the mRNA expression of CLOCK (p<0.01), BMAL1 (p=0.02), CRY1 (p=0.02), PER2 (p<0.01), and PER3 (p<0.01), while no circadian rhythm of PER1, and CRY2 was observed. The expression of PER2 and PER3 genes in control leukocytes showed a late afternoon acrophase at 17.5h (14.9-20.1) and 19.5h (17.9-21.0), respectively, similar to CLOCK gene acrophase at 20.2h (19.0-21.4) while CRY1 showed night acrophase at 22.4h (20.1-24.6) as well as BMAL1 acrophase at 23.6h (21.7-0.49), respectively. In Cushing´s Disease patients, there was a loss of the pattern of clock genes circadian rhythmicity, in concomitance with the loss of cortisol circadian rhythm. One exception was CRY2, which presented a circadian variation (p<0.01), with acrophase during the dark phase at 0.5h (22.5-2.6). Conclusions: Our data suggest that hypercortisolism leads to dysregulation of circadian clock genes expression in Cushing's disease. CRY2 higher expression at night outlines its putative role in the cortisol circadian rhythm disruption. Although the role of clock genes dysregulation in the pathogenesis of Cushing's disease metabolic derangements is still not completely established, it is possible that it synergistically contributes to hypercortisolism to the severity of metabolic features of Cushing's disease. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.