Investigator's Application): Fibromyalgia (FM) and chronic fatigue syndrome (CFS) share many clinical features; however, we believe the difference in the dominant symptomatic manifestations, pain in FM and fatigue in CFS, reflect divergence of their biological phenotype. The onset and course of both syndromes appear to be influenced by physical or emotional stress. The physiologic response to stress is characterized by activation of the hypothalamic-pituitary-adrenal (HPA) axis. Ongoing studies of the HPA axis have uncovered perturbations of the pulsatile and circadian architecture of pituitary-adrenal secretion that may yield clues to the biologic divergence between FM and CFS. The findings in FM suggest psychophysiological arousal, while those in CFS suggest hypoarousal. Both syndromes are also characterized by non-restorative sleep, which is likely to be related, in a bi-directional manner, to the observed HPA axis disturbances. Analysis of the relationships between neuroendocrine secretory patterns and sleep-wake physiology provides a means to test the functional integrity of neural systems responsible for circadian rhythmicity, sleep regulation and hormonal release. The specific hypotheses to be tested in this proposal are: a) HPA axis abnormalities in FM and CFS are mediated centrally at the level of the hypothalamus through failure of integration of neurochemical systems controlling basal and stimulated hormone secretion, b) a relationship exists between mechanisms controlling sleep and HPA axis activity, such that correlations between neuroendocrine and sleep parameters will be present, and c) although abnormal HPA axis activity occurs in both FM and CFS, there are distinctions in the central inputs to the axis resulting in psychophysiological arousal in FM patients and hypoarousal in patients with CFS that may be revealed by close examination of specific components of the HPA axis and provocative testing of sleep architecture. The applicants propose to measure the dynamic pulsatile and circadian characteristics of the basal pituitary adrenal rhythm in FM and CFS patients under the influence of metyrapone, to inhibit glucocorticoid negative feedback and emphasize divergence in the central components of the HPA axis. they will examine the effects of the exogenously administered pituitary corticotroph secretagogues on pituitary-adrenal response in the study groups. They wll analyze sleep regulation and correlate sleep parameters with neuroendocrine hormone secretion. The results of these studies should further our understanding of the role of the HPA axis in the pathogenesis and clinical expression of FM and CFS, enlarge our understanding of the relationship between these two syndromes, and in so doing, make the informed development of reasonable diagnostic approaches and treatment interventions more likely.
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