RLS: Imbalance between thyroid and dopamine Pereira Jr. JC et al. of interest to mention that myxedema coma represents the extreme manifestation of severe hypothyroidism.22 TSH LEVELS, DEEP NREM SLEEP, AND THE AL- PHA SLOW WAVE INDEX OF AROUSAL One important study used concomitant 10-minute TSH blood samplings and polysomnography in young volunteers.25 During normal sleep and recovery sleep after sleep deprivation, the descending slopes of TSH concentrations and the episodes of slow wave sleep (SWS) were selectively associated with each other. Conclusions drawn by the authors were that SWS appeared to be a key factor in the inhibitory effect of sleep on TSH secretion. However, the interpretation of the results of this work is questionable. There is no evidence that SWS inhibits TSH secretion, and the assumption that the decline of TSH values is a permissive condition for the occurrence of SWS seems more logical. A study examining the association between EEG spectral power and concomitant TSH values demonstrated a negative correlation between TSH fluctuations and SWS. 19 This latter study concluded that the descending slopes of TSH levels help enable sleep to reach deep NREM stages. It was also demonstrated that the alpha slow wave index, an index of arousal derived from EEG, coincided with elevations of TSH concentrations.26 The overall nocturnal profile of TSH reflected the importance of high levels of TSH as an arousability factor. The higher the TSH profile, the higher the arousal index. Additionally, Brabant et al.19 and Gronfier et al.26 showed that TH does have a role in sleep modulation (Figure 2). SUMMARY OF THE INTERACTIONS BETWEEN DA, TH AND RLS. TH levels follow DA levels14-16 Thus, the depressing effects of DA on TH are a concern in certain clinical settings.27-29 Thyroid-releasing hormone (TRH) regulates TSH synthesis by stimulating the transcription and translation of the TSH β-subunit gene; dopamine inhibits this process.30 Anti-DA drugs such as metoclopramide aggravate the symptoms of RLS,17 while DA agonists diminish RLS symptoms.31-35 Reduced levels of iron diminish the DA system, which in turn aggravates RLS.10-12, 22 TH axis heightens during sleep deprivation, as demonstrated in voluntary sleep deprivation. 23 Sleep deprivation, in turn, is well known to aggravate RLS symptoms.5 Some of the effects of increased TH, such as hyperthyroidism, resemble some symptoms of RLS patients.21, 22 Opioids, the first class of drugs used to treat RLS,3, 5 are also known to depress the TH axis.36,37 Some drugs that are effective against RLS 550 CLINICS 2010;65(5):547-54 Figure 2 - depicts the proposed relationship between TSH levels with sleep propensity and sleep. Modified from Pannain and Van Cauter 24: “Mean 24-hour profile of plasma TSH during a 53-hour period including 8 hours of nocturnal sleep (black bar), 28 hours of continuous wakefulness (nocturnal hours: white bar), and 8 hours of daytime sleep (black bar at the right). Subjects were young healthy men. The shadow area corresponds to normal 24-hour conditions. The vertical bar at each time point represents the standard error of the mean (SEM) ...” (Pannain S, Van Cauter E. Sleep Medicine Clinics 2007; 2: 147-159). symptoms, such as carbamazepine, phenobarbital, valproate, and primidone are inducers of CYP450 enzyme activity.38 Selective serotonin reuptake inhibitors, neuroleptics, tricyclic antidepressants, and antihistamines are all CYP450 inhibitors,39 and they all worsen the symptoms of an RLS patient.3,5 It is unlikely that the facts above be mere coincidence (Figure 3). Figure 3 - A diagram showing the effects of CYP450 inducers or inhibitors on TH metabolism and the final results of these pharmacological actions on T4 and T3 levels. Thyroid hormones (THs); Thyroxine (T4); Triiodo- thyronine (T3). RLS IN PREGNANCY RLS is more common in pregnant women than in non- pregnant women,5 and endocrinological studies in pregnancy have revealed that TH are up regulated during pregnancy.40 This phenomenon supports the hypothesis proposed here, although it is possible that other conditions might be involved in the greater prevalence of RLS during pregnancy. A recent work showed elevated estradiol plasma levels in RLS pregnant women.41 The authors raised the possibility Copyright © 2010 CLINICS