CLINICS 2010;65(5):547-54 that the augmented estradiol could be a causative factor for RLS. However, as there is no evidence of elevated estradiol in non-pregnant RLS patients, it must be inferred that the causality of elevated estradiol on RLS in pregnancy, is, at best, indirect. The parallel between the augmented hormones TH and estradiol in pregnancy deserves comment. One hormonal effect of estradiol is to increase levels of TH.42 Thus, one possible cause of higher TH levels in pregnancy is the higher levels of estradiol, which suggests that estradiol may indirectly cause symptoms of RLS by increasing TH. If these augmented TH levels are not counterbalanced by the DA system, RLS would appear. It is known that estradiol is a CYP450 inhibitor, and it also is a condition for the thyroid binding globulin to increase.43,44 HYPERTHYROIDISM AND RLS SYMPTOMS An interesting case report from Tan and colleagues (2004) illustrates the correlation between TH levels and low iron levels. A hypothyroid patient with low serum ferritin treated with L-thyroxine developed signs and symptoms of RLS. Upon challenge and withdrawal of L-thyroxine, there was a significant change in the International Restless Legs Syndrome Study Group severity score (26/40 to 6/40), the periodic limb movements in sleep (PLMS) index (20/hour to 10/hour), the number of arousals due to PMLS (59 to 22), sleep efficiency (74 to 85%), and other biochemical parameters 45. As many patients with normal iron levels have RLS, one cannot assume that elevated TH and low iron levels are the main dysregulations that cause RLS. It is, however, possible to infer that this abnormal correlation precipitates or aggravates RLS symptoms. L-thyroxine is usually administered to hypothyroid patients in the morning, which essentially decouples TH levels from the circadian biological clock. Therefore, it is not always possible to observe the fourth diagnostic criterion of the IRLSSG ( worsening of symptoms in the evening and night ). The greater prevalence of RLS in patients with hyperthyroidism over healthy subjects could represent the ultimate proof of the importance of TH on the genesis of RLS. This assumption might not be that straightforward since there are several factors to be considered. For example, one must also take into account the modulation of TH by the DA system, which cannot be assumed to always be impaired. Based on the data we gathered, it is reasonable to conclude that the balance between TH and the DA system is what counts most. It is their relative values, one in relation to another, that are important. Despite the dearth of studies on concomitant hyperthyroidism and RLS, an important study by Tan and colleagues46 emphatically demonstrated that a close Copyright © 2010 CLINICS RLS: Imbalance between thyroid and dopamine Pereira Jr. JC et al. relationship between hyperthyroidism and RLS symptoms does exist. This study examined 125 hyperthyroid patients, 21 hypothyroid patients, and 434 normal subjects (control group). None of the thyroid patients were diagnosed as having RLS as defined by the IRLSSG,7 that is, no patients met all four criteria for the RLS diagnosis. The authors of the study also found that RLS has a low prevalence in Singapore where the study took place, as only one subject amongst the 434 subjects of the control group fulfilled all the criteria for diagnosis of RLS (0.2%). Although any case of RLS has been found amongst the hyperthyroid patients, the authors observed RLS-like symptoms corresponding to the three criteria of the IRLSSG in a significant number of the patients. In normal subjects, 4/434 (0.9%) met the first three diagnostic criteria of RLS, as did 1/21 hypothyroid patients (4.8%), and 11/125 hyperthyroid patients (8.8%).46 These numbers are significant as they seem to substantiate the claim that elevated TH is an inciting condition for RLS-like symptoms. In accordance with the hypothesis dealt with in this paper, it is these authors’ belief that the fourth criterion that defines the RLS diagnosis is a consequence of the circadian increase of the TH axis in the evening. In Graves’ disease, the thyroid gland is dysregulated and TH levels do not follow the circadian TH rhythm of a typical normal subject.47 One can assume that a hyperthyroid patient presenting with three of the four criteria46 that define the disease might not have the disease but rather only symptoms of it. The results from the treatment of the hyperthyroid patients46 were noteworthy. Four patients among the 12 with RLS-like symptoms reported complete resolution of their complaints (33%): three hyperthyroid to euthyroid, and one hypothyroid to euthyroid. The others reported some improvement in their symptoms.46 Only these results, pointed out by TAN and colleagues are significant per se. However, 4 out of 11 patients who were hyperthyroid at the beginning of the treatment and reported some improvement after treatment, were still biochemically hyperthyroid when the results of the treatment were tabulated. Logic permits us to suppose that the results of the treatment would have even been better if the conclusions about the treatment had been drawn after these four hyperthyroid patients had become euthyroid. Moreover, elevated TH is not the only factor that can cause RLS, but it is the inciting condition for the syndrome, not the syndrome on its own. Concerning the relationship between the DA system and thyroid status, the reader is encouraged to review the work of Strawn JR and colleagues.48 FINAL REMARKS The RLS augmentation phenomenon, which is a concern when treating a patient with DA agonists,3,5 could be partly 551