Altered setting of the pituitary-thyroid ensemble in hypocretin-deficient narcoleptic men.
Narcolepsy is a sleep disorder caused by disruption of hypocretin (orexin) neurotransmission. Injection of hypocretin-1 acutely suppresses TRH and TSH release in rats. In contrast, subchronic administration does not appear to affect the hypothalamo-pituitary-thyroid ensemble in animals. We explored (in 7 patients and 7 controls) whether hypocretin deficiency impacts circulating TSH levels and circadian timing of TSH release in narcoleptic humans. Plasma TSH concentration profiles (blood samples taken at 10-min intervals during 24 h) and TSH levels in response to TRH injection were analyzed by Cluster, robust regression, approximate entropy (ApEn), and deconvolution. Circulating TSH levels were lower in patients, which was primarily attributable to lower pulse amplitude and nadir concentrations. TSH secretion correlated positively with mean 24-h leptin levels (R2 = 0.46, P = 0.02) and negatively with amount of sleep (R2 = 0.29, P = 0.048). Pattern-synchrony between 24-h leptin and TSH concentrations was demonstrated by significant cross-correlation and cross-ApEn analyses with no differences between controls and patients. Sleep onset was closely associated with a fall in circulating TSH. Features of diurnal rhythmicity of circulating TSH fluctuations were similar in patients and controls, with the acrophase occurring shortly after midnight. Thyroxine and triiodothyronine concentrations were similar in patients and controls and did not display a diurnal rhythm. The response of plasma TSH levels to TRH was also similar in both groups. Sleep patterns in narcoleptics were significantly disorderly compared with controls, as measured by ApEn (P = 0.006). In summary, circulating TSH concentrations are low in hypocretin-deficient narcoleptic men, which could be attributable to their low plasma leptin levels and/or their abnormal sleep-wake cycle.
Kok
Simon W
SW
Department of General Internal Medicine, Leiden University Medical Center, Leiden, The Netherlands.
Roelfsema
Ferdinand
F
Overeem
Sebastiaan
S
Lammers
Gert Jan
GJ
Frölich
Marijke
M
Meinders
A Edo
AE
Pijl
Hanno
H
D000222:Adaptation, Physiological; D000328:Adult; D000368:Aged; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency*; D008297:Male; D008875:Middle Aged; D009290:Narcolepsy / Q000097:blood*; D009479:Neuropeptides / Q000172:deficiency*; D000068797:Orexins; D010902:Pituitary Gland / Q000378:metabolism*; D012890:Sleep; D013961:Thyroid Gland / Q000378:metabolism*; D013972:Thyrotropin / Q000097:blood*
C000596229:HCRT protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009479:Neuropeptides; D000068797:Orexins; D013972:Thyrotropin