CLINICS 2010;65(5):547-54 BRINGING IDEAS TOGETHER IMBALANCE BETWEEN THYROID HORMONES AND THE DOPAMINERGIC SYSTEM MIGHT BE CENTRAL TO THE PATHOPHYSIOLOGY OF RESTLESS LEGS SYNDROME: A HYPOTHESIS Jose Carlos Pereira Jr.,I Marcia Pradella-Hallinan,II Hugo de Lins PessoaI doi: 10.1590/S1807-59322010000500013 Pereira Jr. JC, Pradella-Hallinan M, Pessoa HL. Imbalance between thyroid hormones and the dopaminergic system might be central to the pathophysiology of restless legs syndrome: a hypothesis. Clinics. 2010;65(5):547-54. Data collected from medical literature indicate that dopaminergic agonists alleviate Restless Legs Syndrome symptoms while dopaminergic agonists antagonists aggravate them. Dopaminergic agonists is a physiological regulator of thyroid-stimulating hor- mone. Dopaminergic agonists infusion diminishes the levels of thyroid hormones, which have the ability to provoke restlessness, hyperkinetic states, tremors, and insomnia. Conditions associated with higher levels of thyroid hormones, such as pregnancy or hyperthyroidism, have a higher prevalence of Restless Legs Syndrome symptoms. Low iron levels can cause secondary Restless Legs Syndrome or aggravate symptoms of primary disease as well as diminish enzymatic activities that are involved in dopaminer- gic agonists production and the degradation of thyroid hormones. Moreover, as a result of low iron levels, dopaminergic agonists diminishes and thyroid hormones increase. Iron therapy improves Restless Legs Syndrome symptoms in iron deprived patients. Medical hypothesis. To discuss the theory that thyroid hormones, when not counterbalanced by dopaminergic agonists, may pre- cipitate the signs and symptoms underpinning Restless Legs Syndrome. The main cause of Restless Legs Syndrome might be an imbalance between the dopaminergic agonists system and thyroid hormones. KEYWORDS: Restless Legs Syndrome, RLS; RLS pathophysiology; Dopamine; TSH; CYP450. Editors Note: This article opens a new section in which experienced authors will contribute a measure of speculative thought on apparently unrelated themes in medical practice. INTRODUCTION Dopamine (DA), when diminished, plays an important role in the pathophysiology of Restless Legs Syndrome (RLS) when decreased DA levels are a primary condition, or a secondary condition as is the case when low iron levels have been identified. It is known that DA agonists alleviate RLS symptoms, and there is medical evidence that DA depresses the thyroid axis, which is a concern in certain clinical settings. The daily profile of thyroid-stimulating-hormone (TSH) I Departamento de Pediatria, Faculdade de Medicina de Jundiaí - São Paulo/ SP, Brazil. II Disciplina de Medicina e Biologia do Sono, Departamento de Psicobiologia, Universidade Federal de São Paulo - São Paulo/SP, Brazil. Email: jhpessoa@terra.com.br Tel: 55 11 4586-4559 Received for publication on December 16, 2009 First review completed on January 08, 2010 Accepted for publication on February 17, 2010 levels resembles the daily circadian intensity profile of symptoms of an RLS patient. Levels of TSH increase in the evening, as does the severity of RLS symptoms. To date, DA agonists have been considered to be the best therapy for RLS disturbances. In addition, the DA system modulates thyroid hormones (TH). One mechanism by which TH is modulated by the DA system is through enhancement of the biochemical functions of the complex family of the cytochrome P450 (CYP450) enzymes. In addition, DA and DA agonists inhibit TSH secretion. The CYP450 enzymes are heme enzymes (all have iron) and the CPY450 enzyme superfamily is important for the biochemical degradation of TH. However, low iron levels diminish the quantity of CYP450 available to degrade TH. Several drugs that alleviate the symptoms of RLS are inducers of CYP450 activity, as induced CYP450 activity leads to enhanced degradation activity, causing TH levels to diminish. RLS, also called Ekbom’s syndrome, is a sensorimotor Copyright © 2010 CLINICS – This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons. org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.