CLINICS 2010;65(5):547-54 sleep period. In sequence, TSH levels progressively diminish throughout the sleep period until they reach their low daytime values. The circadian trough of TSH levels normally occurs between midday and 6 pm.19 Sleeping is not impossible out of the sleep phase, but the propensity to sleep usually varies significantly during the period between 7 am and 11 pm. The greatest propensity to sleep occurs in the mid-afternoon, which coincides with the circadian trough of TSH levels. The lowest propensity to sleep is in the evening during the steep circadian increase in TSH levels.20 Notably, the worsening of the symptoms of a typical RLS patient also occurs in the evening (fourth criterion of the IRLSSG).1,7 The parallel between the evening increase of TSH levels and the “worsening RLS symptoms” is of the utmost importance when considering the plausibility of the hypothesis proposed in this paper. The higher propensity to sleep when TSH levels are low, and the lower propensity to sleep when TSH levels are increasing could be a mere coincidence; however, considering that the effect of TH is to decrease the ability to sleep, even resulting in insomnia, and that diminished TH cause somnolence,21,22 it is likely that there is a causal relationship between TSH levels and RLS (Figure 2). Analyzing plots of TSH values over a 24-hour period and the relationship of the curve to sleep phase or sleep propensity can contribute to our understanding certain circadian characteristics of the sleep-wake rhythm. These characteristics include the propensity to sleep, sleep itself, arousabilty from sleep, and voluntary or involuntary sleep deprivation. It has previously been held that the waveform of the daily profile values of TSH is influenced by sleep.19,23,24 This interpretation might not be totally accurate, as inference from the physiological and therapeutics effects of thyroid hormones (activity inducers) suggest that TSH levels influence sleep and not the contrary. In other words, the daily circadian waveform of thyrotropin could well be titled “The Thyroid Axis and Sleep”, instead of “Sleep and the Thyroid Axis”.The effects of TH are more likely to promote sleeplessness rather than sleepiness.21,22 Also relevant to this line of reasoning is the fact that the greatest propensity for sleep occurs during the circadian trough of the TSH waveform, from mid- to late-afternoon 20. Could this heightened “propensity-for-sleep,” rather than sleep itself, be responsible for the declining TSH values and the circadian trough of TSH? Could “sleep propensity” be a modulating condition of TSH? The possibility that the “low propensity for sleep” 20 associated with the early evening is responsible for the steep increase in TSH levels (TSH surge) is also unlikely. Could “propensity-to-sleep” be considered a “function” that possibly modulates other functions? The idea that sleep deprivation relieves the inhibitory effects of sleep on TSH levels 23 is not correct. A more Copyright © 2010 CLINICS RLS: Imbalance between thyroid and dopamine Pereira Jr. JC et al. reasonable interpretation of the relationship between TSH level and sleep is that sleep deprivation is made possible by the elevation of TH, not the reverse. As sleep deprivation is an abnormal condition, contrary to sleep-wake homeostasis, it is logical to infer that some function (or functions) must be executed to enable the curtailment of sleep. Considering the physiological and pharmacological profiles of TH, they can be mainly considered as hormones inhibitors of sleep. In this light, TSH levels are important in modulating sleep propensity. During the biological day, the propensity for sleep is low in the late morning,20 a period when TSH levels are higher than during late afternoon. The fact that it is much more difficult to maintain wakefulness in the second half of the biological night,20 when TSH levels are lower than in the first half, needs to be factored into any understanding of these phenomena. From clinical RLS grounds it is well known that the best period for an RLS patient to sleep is in the early morning, which coincides with lower levels of TSH. It is also well known from clinical and pharmacology studies that sleep attack is a concerning side effect of DA therapy.3,5 A reasonable explanation for this fact is that DA therapy depresses TH,16 which are responsible for maintaining the alertness of wakefulness. It is equally important to analyze the interaction between TSH levels and sleep during the sleep phase. After sleep onset, TSH levels remain high during the night compared to daytime values. After reaching peak around sleep onset, TSH levels progressively decrease throughout the sleep phase towards low daytime values.19 In the case of sleep deprivation, this nocturnal decline is not observed.23 Apparently there is a paradox with regard to the fact that TSH levels are higher during the sleep phase than during wakefulness, but this is likely not without explanation: at the onset of sleep, the circadian rhythm imposes its sleep drive and the individual starts sleeping; during sleep there is a dramatic decline in the sleeping person’s alertness, but there remains an arousability condition inherent to the sleep state, critical for survival purposes. The physiological and clinical profiles of TH suggest that TH comprise the putative system that permits arousability from the sleep state. F r o m c l i n i c a l s e t t i n g s , i t i s w e l l k n ow n t h a t hypothyroidism causes a low level of alertness and somnolence in patients. While the arousability condition inherent to the sleep state may involve additional systems, robust evidence in medical science leads us to posit that TH is very important to this biological phenomenon. The reason that TSH levels are depressed during wakefulness compared to the sleep phase can be logically explained by the following: the wakefulness state inherently maintains higher alertness, driven by circadian rhythmicity; thus necessitating lower TH levels. Some TH is needed, however, to prevent sleep from transforming into a coma state. It is 549