0341 Impaired Negative Feedback of the Hypothalamic-Pituitary-Adrenal Axis in Chronic Insomnia: A Corticotrophin Releasing Hormone (CRH) Challenge Test

Abstract

Introduction: Insomnia, particularly the short sleep phenotype, has been associated with activation of the hypothalamic-pituitary-adrenal (HPA) axis. Recent studies using challenge tests such as the Trier Social Stress Test (TSST) have suggested a blunted cortisol response in subjects with insomnia. However, no study to date has used a physiologic challenge of the HPA axis, via exogenous administration of corticotrophin releasing hormone (CRH), to replicate those findings without the intervening role of appraisal/coping that mediate the response to the TSST. Methods: Adrenocorticotropic hormone (ACTH) and cortisol levels were assayed before (-30min, -15min), at (0min), and after (+5min, +15min, +30min, +60min, +90min and +120min) exogenous CRH administration in 22 men (46.4 ± 9.0 years) with and without clinically diagnosed insomnia who underwent 4 consecutive nights of in-lab polysomnography. Multivariate analyses of covariance adjusted for ACTH and cortisol levels before CRH administration. Results: Compared to controls (n=11), insomniacs (n=11) showed lower ACTH and cortisol levels after CRH administration (e.g., 41.9 ± 4.5 vs. 27.9 ± 4.5 ug/dL and 19.9 ± 1.1 vs. 16.2 ± 1.1 ug/dL, respectively, p<0.05). Importantly, insomniacs with short sleep duration (n=9) showed higher ACTH levels before CRH administration (e.g., 6.4 ± 1.3 vs. 11.6 ± 1.0 ug/dL, p<0.05) and lower cortisol levels after CRH administration (e.g., 22.4 ± 1.6 vs. 15.5 ± 1.2 ug/dL, p<0.05). Conclusion: Our data showed a blunted response to the CRH test in men with chronic insomnia, primarily driven by those with objective short sleep duration. These data suggest an impaired negative feedback of the HPA axis in men with severe chronic insomnia and may be a consequence of chronic physiological wear-and-tear. These data may predict inadequate response to physiological or behavioral stressors, poor coping over time and predisposition to emotional (i.e., depression) and physical (i.e., cardiovascular) problems. Our data pin-point the need of developing treatments targeting the underlying HPA axis dysregulation to decrease physiologic hyperarousal, increase sleep duration, and, potentially, lower emotional and cardiometabolic risk.