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Dynamics of the Pituitary-Adrenal Ensemble in Hypocretin-Deficient Narcoleptic Humans: Blunted Basal Adrenocorticotropin Release and Evidence for Normal Time-Keeping by the Master Pacemaker

Departments of General Internal Medicine (S.W.K., M.F., A.E.M., H.P.), Endocrinology (F.R.), and Neurology (S.O., G.J.L.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; and Department of Clinical Neurophysiology, University Hospital Vrije Universiteit (R.L.S.), 1094 LM Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: S. W. Kok, M.D., Department of General Internal Medicine (C1-R38), Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. E-mail: s.w.kok{at}lumc.nl.

Abstract

Narcolepsy is a sleep disorder caused by disruption of hypocretin (orexin) neurotransmission. It has been suggested that anomalous timing by the biological clock contributes to the symptomatology. Hypocretins stimulate the pituitary-adrenal (PA) axis in rodents. We explored whether hypocretin deficiency disrupts circadian timing and blunts PA hormone release. We deconvolved 24-h plasma profiles of ACTH and cortisol, and determined their circadian rhythm by cosinor analysis in seven hypocretin-deficient narcoleptic males and seven matched controls. Basal and total ACTH production were blunted in narcoleptics [310 ± 86 vs. 760 ±160 ng/liter·24 h (P = 0.02) and 920 ± 147 vs. 1460 ± 220 ng/liter·24 h (P = 0.04), respectively], whereas pulsatile release did not differ between groups. In contrast, basal, pulsatile and total cortisol secretion were similar in both groups. The cross-approximate entropy of the joint ACTH/cortisol time series was higher in narcoleptics (1.26 ± 0.07 vs. 1.07 ± 0.04; P = 0.04), reflecting reduced secretory process regularity. The acrophases of both ACTH and cortisol occurred at similar clock times (0830 h) in patients and controls, which supports the idea that the master pacemaker is intact in narcolepsy. The reduced (basal) ACTH secretion and the diminished secretory process regularity of the ACTH/cortisol ensemble conjointly suggest that hypocretin deficiency induces changes in the interplay between PA hormones.

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