Diplomová práce Miroslav Zůna 3 Author's first name and surname: Miroslav Zůna, BA. Title of the master thesis: Changes of thermal thresholds in patients treated with hypothyroidism. Department: Department of Physiotherapy and Sports Medicine Supervisor: Hana Marčišová, MA. The year of presentation: 2013 Abstract: Disorders of thyroid gland together with diabetes are most common endocrine diseases in Czech Republic and worldwide, too. Myopathy and neuropathy, caused by reduced amount of thyroid hormones, are mentioned in current literature, however pathaphysiological mechanisms stay unclear. To evaluate the state of small nerve fibers that should be affected first, we use thermal threshold testing, setting the thermal threshold for warm and cold stimuli in different locations. Patients with hypothyroidism show in most of the measured locations higher thermal threshold than that of the control group, however these results are not significant. Significant change of thermal sensation of cold stimulus is demonstrated in location thenar. Patients with hypothyroidism also have a higher degree of inaccuracy detection of thermal stimuli. A greater number of significant conclusions can not seem to reach for a small number of probands participating in our study or due to ongoing therapy and the resulting normal state...

Introdução: As disfunções tireoidianas subclínicas são comuns na prática clínica, particularmente entre mulheres de meia idade. Existem algumas evidências de que as disfunções tireoidianas subclínicas podem afetar o risco cardiovascular de forma negativa, além de afetar a qualidade de vida e produzir sintomas somáticos e psicológicos. Entretanto ainda existe muita controvérsia sobre se o tratamento destas disfunções afeta positivamente algum desfecho clínico e se estaria indicado realizar um rastreamento populacional destas disfunções. Objetivo: Este estudo teve como objetivo determinar a freqüência das disfunções tireoidianas subclínicas e sua associação com fatores de risco cardiovasculares tradicionais e com alguns fatores psico-sociais em mulheres com 40 anos ou mais em seu local de trabalho. Métodos: Estudo transversal de rastreamento com funcionárias da Universidade de São Paulo com 40 anos ou mais. Todas as participantes foram entrevistadas e responderam a quatro questionários específicos validados [um questionário sobre características sócio-demográficas, o questionário de angina de Rose, o Short Form Health Survey - 36 (SF-36) e o Self-Report Questionnaire (SRQ-20)], foram submetidas a mensuração de medidas antropométricas e da pressão arterial e tiveram uma amostra de sangue colhida para avaliação de função tireoidiana (TSH e T4-livre) e anticorpos antitireoperoxidase (anti-TPO), glicemia de jejum e colesterol total, LDL-colesterol e HDL-colesterol. Em uma subamostra do estudo também foi dosada a proteína C ultra-sensível (hsCPR). As mulheres foram analisadas de acordo com seu estado funcional tireoidiano. Resultados: Das 736 funcionárias com 40 anos ou mais convidadas a participar, 314 (42,7%) aceitaram o convite. As freqüências de hipotireoidismo e hipertireoidismo subclínico foram, respectivamente, 7,3% e 5,1%. Anticorpos anti-tireoperoxidase positivos foram encontrados em 51 mulheres (16,2%). Níveis de TSH < 10 mIU/l estavam presentes em 78,3% das mulheres com hipotireoidismo subclínico. Não houve diferença nas características gerais, nos fatores de risco para doença cardiovascular, nos fatores psico-sociais nem, de uma forma geral, na qualidade de vida comparando-se as mulheres de acordo com sua função tireoidiana. Conclusão: Não se encontrou nenhuma associação entre disfunção tireoidiana subclínica e fatores de risco para doença cardiovascular. Não se encontrou nenhuma associação de disfunção tireoidiana subclínica e fatores psico-sociais (qualidade de vida, sintomas somáticos e psicológicos). Os resultados deste estudo transversal não suportam a prática de rastreamento rotineiro de disfunção tireoidiana subclínica. / Rational: Subclinical thyroid dysfunction is very common in clinical practice, particularly among middle-aged women. There is some evidence that subclinical thyroid dysfunction may affect cardiovascular risk in a negative fashion, and also affect quality of life and produce somatic and psychological symptoms. There remains much controversy as whether there should be a population based screening for these dysfunctions and whether treatment of these dysfunctions have any positive impact on clinical outcomes. Objective: The aim of this study was to determine the approximate frequency of subclinical thyroid dysfunction and its association with traditional cardiovascular risk factors as well as some psychosocial factors in women 40 years of age or older at the worksite. Methods: Cross-sectional screening study with women 40 years of age or older, working at the University of São Paulo. All the women answered four specific questionnaires [a questionnaire on socio-demographic characteristics, the Rose Angina Questionnaire, the Short Form Health Survey -36 (SF-36) and the Self- Report Questionnaire (SRQ-20)], had antropometric variables and blood pressure measured, and blood analyzed for total-cholesterol, LDL-cholesterol, HDL-cholesterol, tryglicerides, fasting glucose, thyroid-stimulating hormone (TSH), free-thyroxine (free-T4) and anti-thyreoperoxidase antibodies (anti-TPO). In a sub-sample of these women high-sensitive C reactive protein (hsCRP) was measured. Women were analyzed according to their thyroid function status. Results: Of the 736 women invited to participate, 314 (42.7%) accepted the invitation. The frequencies of subclinical hypothyroidism and subclinical hyperthyroidism were, respectively, 7.3% and 5.1%. Positive antibodies against thyreoperoxidase were present in 51 women (16.2%). TSH levels < 10 mIU/l were present in 78.3% of women with subclinical hypothyroidism. There was no difference in general characteristics, cardiovascular risk factors, psychosocial factors nor, in a general way, in quality of life among these women according to their thyroid function status. Conclusion: No association between cardiovascular risk factors and subclinical thyroid dysfunction was found. No association between subclinical thyroid dysfunction and psychosocial factors (quality of life, somatic and psychological symptoms) was found either. The results of this cross-section study do not support the routine screening of subclinical thyroid dysfunction.

INTRODUÇÂO: A tireoidite crônica autoimune (TCA) é a principal causa de hipotireoidismo adquirido, o qual requer tratamento contínuo com levotiroxina (LT4). Até o momento, não há terapia capaz de regenerar o tecido tireóideo lesado e melhorar sua função. Como a terapia com Laser de baixa intensidade (LILT) foi eficaz em outras doenças autoimunes, bem como na regeneração de vários tecidos, o objetivo deste estudo foi avaliar a eficácia do Laser de baixa intensidade no tratamento de pacientes com hipotireoidismo decorrente de tireoidite crônica autoimune utilizando-se os seguintes parâmetros de resposta: a) o mapeamento dúplex-Doppler colorido da tireoide; b) a função tireóidea estimada pela dose de LT4 necessária para manter as concentrações séricas de T3 total, T4 total, T4 livre e TSH normais; c) as concentrações séricas de anticorpos antiperoxidase tireóidea (TPOAb) e antitireoglobulina (TgAb). MÉTODOS: Trata-se de ensaio clínico randomizado, placebo-controlado, conduzido no Instituto de Radiologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, de março de 2006 a março de 2009, no qual foram incluídos 43 pacientes com hipotireoidismo causado por TCA. Todos eles apresentavam altas concentrações séricas de TPOAb e/ou TgAb e padrão ultrassonográfico compatível com TCA. Os pacientes foram randomizados em grupo L (submetido à LILT, n = 23) e P (submetido ao placebo, n = 20). Os limites da tireoide foram demarcados com o auxílio da ultrassonografia. Pacientes do grupo L submeteram-se à LILT (830 nm) e os do grupo P à função placebo do mesmo equipamento. Ambos os grupos foram submetidos, no total, à 10 sessões, duas vezes por semana, com a mesma técnica. Realizou-se pré e 30 dias pós-intervenção: o estudo ultrassonográfico (US) pelo modo-B, que incluiu o histograma computadorizado de escala de cinzas para estimar quantitativamente o índice de ecogenicidade; o US-Doppler colorido de amplitude atribuindo-se valores de 0 a 4 para os padrões de vascularização e o US-Doppler pulsado para estimar a velocidade de pico sistólico e o índice de resistividade das artérias tireóideas superiores e inferiores. Após o segundo US, os pacientes descontinuaram a LT4, a qual foi reintroduzida para os pacientes que apresentaram hipotireoidismo, em dose suficiente para obter normalização hormonal. Realizaram-se determinações séricas de T3 total, T4 total, T4 livre, TSH, TPOAb e TgAb pré-intervenção e no 1º, 2º, 3º, 6º e 9º meses pós-suspensão de LT4. RESULTADOS: No US modo-B pós-intervenção, verificou-se aumento estatisticamente significativo do índice de ecogenicidade no grupo L (1,24 ± 0,11) comparado ao P (0,98 ± 0,07; P < 0,001), assim como a proporção de pacientes com volume normal foi estatisticamente maior no grupo L (P = 0,005). O US-Doppler colorido de amplitude mostrou que o valor do padrão de vascularização foi estatisticamente maior no grupo P (2,3 ± 0,27) do que no L (1,87 ± 0,36; P = 0,033). Observou-se redução da dose de LT4 no grupo L (38,59 ± 20,22 g/dia) comparada à do P (106,88 ± 22,9 g/dia; p < 0,001). TPOAb foi menor no grupo L (681,91 ± 317,44 U/mL) do que no P (1176,40 ± 551,9 U/mL; p = 0,043). Não houve redução de TgAb e efeitos adversos. CONCLUSÕES: A LILT foi eficaz no tratamento da TCA, uma vez que no grupo L verificou-se: a) melhora da ecogenicidade, do volume e do padrão de vascularização da glândula tireoide no mapeamento dúplex-Doppler colorido; b) melhora da função da glândula tireoide, evidenciada pela redução da dose de LT4 necessária para tratar o hipotireoidismo c) modulação parcial da autoimunidade, demonstrada por meio da redução das concentrações séricas de TPOAb / INTRODUCTION: A chronic autoimmune thyroiditis (CAT) is the main cause of acquired hypothyroidism which requires continuous treatment with levothyroxine (LT4). So far there has been no such therapy which can make the damaged thyroid tissue regenerate, improving its function. As the low-intensity Laser therapy (LILT) was effective in other autoimmune diseases, as well as in regenerating several tissues, the objective of this study was to evaluate the efficacy of LILT in patients with hypothyroidism caused by CAT by utilizing the following response parameters: A) Color Doppler ultrasonography of thyroid; B) The thyroid function estimated by the dose of LT4 in order to keep the serum concentrations of normal T3, T4, free T4 (fT4) and TSH; C) The serum concentrations of thyroid peroxidase (TPOAb) and thyroglobulin antibodies (TgAb). METHODS: This is a placebo-controlled randomized clinical essay guided at the Institute of Radiology, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo from March 2006 to March 2009, made up of 43 patients with hypothyroidism caused by CAT. All the patients showed high serum concentrations of TPOAb and/or TgAb and ultrasound pattern compatible with CAT. The patients were randomized in L group (submitted to LILT, n = 23) and P group (submitted to placebo, n = 20). The limits of thyroid were marked off with the help of ultrasonography. The patients in L group were submitted to LILT (830 nm) and the patients in P group were submitted to the placebo function of the same equipment. Both groups were submitted a total of 10 sessions, twice a week, using the same technique. Pre- and 30 days post-intervention were applied: ultrasonographic study (US) by B-mode, which included the grey scale computerized histogram to quantitatively estimate the index of echogenicity; the amplitude color Doppler US with values given from 0 to 4 for the vascularization patterns and the pulsed Doppler US to estimate the systolic peak velocity and the index of resistivity of superior and inferior thyroid arteries. After the second US the patients discontinued the LT4, which was later re-introduced in the patients having hypothyroidism in a certain amount so as to be sufficient to obtain hormonal normalization. Serum determinations of total T3, total T4, fT4, TSH, TPOAb and TgAb pre-intervention were accomplished and also in the 1st, 2nd, 3rd, 6th and 9th month post-suspension of LT4. RESULTS: In post-intervention B-mode US a significant increase in the index of echogenicity in L group (1.24 ± 0.11) was statistically observed compared with the P group (0.98 ± 0.07; P < 0.001), as well as the proportion of patients with normal volume was shown statistically higher in L group (P = 0.005). The amplitude color Doppler US showed the standard value of vascularization was statistically greater in P group (2.3 ± 0.27) than in L group (1.87 ± 0.36; P = 0.033). Pulsed Doppler US showed an increase in the systolic peak velocity of the inferior thyroid arteries in L group (34.47 ± 4.81 cm/s) in relation to P group (26.12 ± 4.29 cm/s; P = 0.016). A reduction in the dose of LT4 in L group (38.59 ± 20.22 g/day) was observed compared with the one in P group (106.88 ± 22.9 g/day; p < 0.001). TPOAb was smaller in L-group (681.91 ± 317.44 U/mL) than in P-group (1176.40 ± 551.9 U/mL; p = 0.043). There was no reduction of TgAb and adverse effects. CONCLUSIONS: LILT was effective in the treatment of CAT, once L group showed: A) amelioration of echogenicity, of volume and of vascularization of the thyroid gland in the color Doppler ultrasonography; B) improvement of thyroid function, featured through the reduction in the necessary dose of LT4 to treat the hypothyroidism; C) partial modulation of autoimmunity demonstrated by reduction of TPOAb serum concentrations

INTRODUÇÂO: A tireoidite crônica autoimune (TCA) é a principal causa de hipotireoidismo adquirido, o qual requer tratamento contínuo com levotiroxina (LT4). Até o momento, não há terapia capaz de regenerar o tecido tireóideo lesado e melhorar sua função. Como a terapia com Laser de baixa intensidade (LILT) foi eficaz em outras doenças autoimunes, bem como na regeneração de vários tecidos, o objetivo deste estudo foi avaliar a eficácia do Laser de baixa intensidade no tratamento de pacientes com hipotireoidismo decorrente de tireoidite crônica autoimune utilizando-se os seguintes parâmetros de resposta: a) o mapeamento dúplex-Doppler colorido da tireoide; b) a função tireóidea estimada pela dose de LT4 necessária para manter as concentrações séricas de T3 total, T4 total, T4 livre e TSH normais; c) as concentrações séricas de anticorpos antiperoxidase tireóidea (TPOAb) e antitireoglobulina (TgAb). MÉTODOS: Trata-se de ensaio clínico randomizado, placebo-controlado, conduzido no Instituto de Radiologia do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, de março de 2006 a março de 2009, no qual foram incluídos 43 pacientes com hipotireoidismo causado por TCA. Todos eles apresentavam altas concentrações séricas de TPOAb e/ou TgAb e padrão ultrassonográfico compatível com TCA. Os pacientes foram randomizados em grupo L (submetido à LILT, n = 23) e P (submetido ao placebo, n = 20). Os limites da tireoide foram demarcados com o auxílio da ultrassonografia. Pacientes do grupo L submeteram-se à LILT (830 nm) e os do grupo P à função placebo do mesmo equipamento. Ambos os grupos foram submetidos, no total, à 10 sessões, duas vezes por semana, com a mesma técnica. Realizou-se pré e 30 dias pós-intervenção: o estudo ultrassonográfico (US) pelo modo-B, que incluiu o histograma computadorizado de escala de cinzas para estimar quantitativamente o índice de ecogenicidade; o US-Doppler colorido de amplitude atribuindo-se valores de 0 a 4 para os padrões de vascularização e o US-Doppler pulsado para estimar a velocidade de pico sistólico e o índice de resistividade das artérias tireóideas superiores e inferiores. Após o segundo US, os pacientes descontinuaram a LT4, a qual foi reintroduzida para os pacientes que apresentaram hipotireoidismo, em dose suficiente para obter normalização hormonal. Realizaram-se determinações séricas de T3 total, T4 total, T4 livre, TSH, TPOAb e TgAb pré-intervenção e no 1º, 2º, 3º, 6º e 9º meses pós-suspensão de LT4. RESULTADOS: No US modo-B pós-intervenção, verificou-se aumento estatisticamente significativo do índice de ecogenicidade no grupo L (1,24 ± 0,11) comparado ao P (0,98 ± 0,07; P < 0,001), assim como a proporção de pacientes com volume normal foi estatisticamente maior no grupo L (P = 0,005). O US-Doppler colorido de amplitude mostrou que o valor do padrão de vascularização foi estatisticamente maior no grupo P (2,3 ± 0,27) do que no L (1,87 ± 0,36; P = 0,033). Observou-se redução da dose de LT4 no grupo L (38,59 ± 20,22 g/dia) comparada à do P (106,88 ± 22,9 g/dia; p < 0,001). TPOAb foi menor no grupo L (681,91 ± 317,44 U/mL) do que no P (1176,40 ± 551,9 U/mL; p = 0,043). Não houve redução de TgAb e efeitos adversos. CONCLUSÕES: A LILT foi eficaz no tratamento da TCA, uma vez que no grupo L verificou-se: a) melhora da ecogenicidade, do volume e do padrão de vascularização da glândula tireoide no mapeamento dúplex-Doppler colorido; b) melhora da função da glândula tireoide, evidenciada pela redução da dose de LT4 necessária para tratar o hipotireoidismo c) modulação parcial da autoimunidade, demonstrada por meio da redução das concentrações séricas de TPOAb / INTRODUCTION: A chronic autoimmune thyroiditis (CAT) is the main cause of acquired hypothyroidism which requires continuous treatment with levothyroxine (LT4). So far there has been no such therapy which can make the damaged thyroid tissue regenerate, improving its function. As the low-intensity Laser therapy (LILT) was effective in other autoimmune diseases, as well as in regenerating several tissues, the objective of this study was to evaluate the efficacy of LILT in patients with hypothyroidism caused by CAT by utilizing the following response parameters: A) Color Doppler ultrasonography of thyroid; B) The thyroid function estimated by the dose of LT4 in order to keep the serum concentrations of normal T3, T4, free T4 (fT4) and TSH; C) The serum concentrations of thyroid peroxidase (TPOAb) and thyroglobulin antibodies (TgAb). METHODS: This is a placebo-controlled randomized clinical essay guided at the Institute of Radiology, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo from March 2006 to March 2009, made up of 43 patients with hypothyroidism caused by CAT. All the patients showed high serum concentrations of TPOAb and/or TgAb and ultrasound pattern compatible with CAT. The patients were randomized in L group (submitted to LILT, n = 23) and P group (submitted to placebo, n = 20). The limits of thyroid were marked off with the help of ultrasonography. The patients in L group were submitted to LILT (830 nm) and the patients in P group were submitted to the placebo function of the same equipment. Both groups were submitted a total of 10 sessions, twice a week, using the same technique. Pre- and 30 days post-intervention were applied: ultrasonographic study (US) by B-mode, which included the grey scale computerized histogram to quantitatively estimate the index of echogenicity; the amplitude color Doppler US with values given from 0 to 4 for the vascularization patterns and the pulsed Doppler US to estimate the systolic peak velocity and the index of resistivity of superior and inferior thyroid arteries. After the second US the patients discontinued the LT4, which was later re-introduced in the patients having hypothyroidism in a certain amount so as to be sufficient to obtain hormonal normalization. Serum determinations of total T3, total T4, fT4, TSH, TPOAb and TgAb pre-intervention were accomplished and also in the 1st, 2nd, 3rd, 6th and 9th month post-suspension of LT4. RESULTS: In post-intervention B-mode US a significant increase in the index of echogenicity in L group (1.24 ± 0.11) was statistically observed compared with the P group (0.98 ± 0.07; P < 0.001), as well as the proportion of patients with normal volume was shown statistically higher in L group (P = 0.005). The amplitude color Doppler US showed the standard value of vascularization was statistically greater in P group (2.3 ± 0.27) than in L group (1.87 ± 0.36; P = 0.033). Pulsed Doppler US showed an increase in the systolic peak velocity of the inferior thyroid arteries in L group (34.47 ± 4.81 cm/s) in relation to P group (26.12 ± 4.29 cm/s; P = 0.016). A reduction in the dose of LT4 in L group (38.59 ± 20.22 g/day) was observed compared with the one in P group (106.88 ± 22.9 g/day; p < 0.001). TPOAb was smaller in L-group (681.91 ± 317.44 U/mL) than in P-group (1176.40 ± 551.9 U/mL; p = 0.043). There was no reduction of TgAb and adverse effects. CONCLUSIONS: LILT was effective in the treatment of CAT, once L group showed: A) amelioration of echogenicity, of volume and of vascularization of the thyroid gland in the color Doppler ultrasonography; B) improvement of thyroid function, featured through the reduction in the necessary dose of LT4 to treat the hypothyroidism; C) partial modulation of autoimmunity demonstrated by reduction of TPOAb serum concentrations

Les hormones thyroïdiennes sont importantes à la fois pour le développement, la maturation et le fonctionnement du système nerveux central tout au long de la vie. Alors que l’association entre l’absence d’hormones thyroïdiennes dans l’hypothyroïdie congénitale et le retard mental profond est bien documentée, l’hypothyroïdie acquise à l’âge adulte peut se manifester par une variété de symptômes tant somatiques, que neuropsychologiques ou psychiatriques comme des troubles de l’attention, troubles de la concentration, troubles de mémoire, un ralentissement psychomoteur mais aussi une humeur dépressive, de l’anxiété et même parfois un délire de persécution. De plus, les processus physiopathologiques reliant l’activité thyroïdienne à ces symptômes restent peu clairs dans l’hypothyroïdie acquise à l’âge adulte. L’objectif de cette thèse est d’examiner les relations entre état hypothyroïdien et dépression. En utilisant des échelles psychométriques, dix patients thyroïdectomisés pour carcinome thyroïdien ont été évalués pour la dépression, l’anxiété et le ralentissement psychomoteur ; ils ont été examinés à la fois en eu- et hypothyroïdie après retrait des hormones thyroïdiennes. Une tomographie par émission de positrons a été utilisée, avec de l’eau marquée à l’oxygène-15 et du fluorodéoxyglucose marqué au fluor-18 comme traceurs, de manière à corréler le débit sanguin cérébral régional (rDSC) et le métabolisme cérébral au glucose (rMGC) avec l’état mental des patients. Deux techniques différentes d’analyse d’images ont été appliquées (régions d’intérêt et cartes statistiques paramétriques). En hypothyroïdie, il y avait une diminution généralisée du rDSC (23.4%, p<0.001) et du rMGC (12.1%, p<0.001) sans diminution locale spécifique. Les patients étaient aussi significativement plus déprimés (p<0.001), plus anxieux (p<0.001) et plus ralentis sur le plan psychomoteur (p<0.005) en hypothyroïdie qu’à l’état euthyroïdien. Ces résultats indiquent que l’activité cérébrale est globalement réduite en hypothyroïdie sévère de courte durée sans observation des modifications régionales habituellement décrites dans la dépression majeure. Nous avons ensuite conduit une étude cognitive qui a examiné les fonctions attentionnelles, mnésiques et exécutives de même que l’intensité des symptômes anxieux et dépressifs dans l’état hypothyroïdien et le trouble dépressif majeur et le lien possible entre ces symptômes et les perturbations cognitives. Cette étude a confirmé l’existence d’un ralentissement psychomoteur associé à des perturbations attentionnelles et exécutives mais non mnésiques dans la dépression majeure, de même que dans l’hypothyroïdie. Cependant, alors que les patients déprimés présentaient un biais conscient pour du matériel à valence émotionnelle négative, ce biais n’a pas été observé chez les patients hypothyroïdiens. Alors que l’état hypothyroïdien s’accompagnait de symptômes anxieux et dépressifs, il semble que ces derniers soient trop discrets pour qu’un biais attentionnel puisse être observé avec du matériel à valence émotionnelle négative. En conclusion, les perturbations cognitives observées en hypothyroïdie semblent être directement reliées à cette condition métabolique hypothyroïdienne plutôt que la conséquence des symptômes dépressifs associés à cette condition. / The thyroid hormone is important both for the functional development and maturation of the central nervous system and for its proper functioning throughout life. Whereas the association between the absence of thyroid hormone in congenital hypothyroidism and profound mental retardation is well documented, adult onset hypothyroidism may have a variety of somatic, neuropsychological and psychiatric symptoms such as inattentiveness, inability to concentrate, deficits in memory, psychomotor slowing but also depressive mood state, anxiety, and sometimes persecutive delusions. In addition, the pathophysiological process relating thyroid activity to these symptoms remain unclear in adult onset hypothyroidism. The objective of this thesis is to examine the relationships between hypothyroidism and depression. Using psychometric scales, ten patients that had undergone total thyroidectomy for thyroid carcinoma were evaluated for depression, anxiety and psychomotor slowing; they were examined both when euthyroid and hypothyroid after thyroid hormone withdrawal. Positron emission tomography was used, with oxygen-15-labeled water and fluorine-18 FDG as the tracers, to correlate the regional cerebral blood flow (rCBF) and cerebral glucose metabolism (rCMRGlc) with the mental state in patients. Two different image analysis techniques (regions of interest and statistical parametric maps) were applied. In hypothyroidism, there was a generalized decrease in rCBF (23.4%, p<0.001) and in rCMRGlc (12.1%, p<0.001) and there were no specific local defects. Patients were also significantly more depressed (p<0.001), anxious (p<0.001) and psychomotor slowed (p<0.005) in hypo- than in euthyroid status. These results indicate that the brain activity was globally reduced in severe hypothyroidism of short duration without the regional modifications usually observed in primary depression. We conducted then a cognitive study which examined attentional, mnemonic and executive functions as well as the intensity of anxiety and depressive symptoms in hypothyroidism and major depression and the possible link between these symptoms and cognitive disturbances. This study confirmed the existence of psychomotor slowing associated with attentional and executive disturbance but without mnemonic disturbances in major depression as well as in hypothyroidism. However, while depressed subjects manifested a conscious bias with material of negative emotional valence, no such bias was found in the hypothyroid subjects. While the hypothyroid state is accompanied by anxiety/depressive symptoms, it seems that the latter are too discrete for an attentional bias to be observed with material with a negative emotional valence. In conclusion, the cognitive disturbances observed in hypothyroidism seem to be directly related to the metabolic condition of hypothyroidism rather than the consequence of the depressive symptoms associated with this condition.

Hypothyroidism is a common endocrine disorder affecting women of reproductive age. On a global level, iodine deficiency is still the most common cause of hypothyroidism. Also genetic variations, in particular SNP rs4704397 in the PDE8B gene, are responsible for a significant proportion of TSH variations.  Untreated hypothyroidism has significant adverse effects on pregnancy and fetal outcome. Most international guidelines suggest targeted thyroid testing in pregnant women with risk factors for thyroid disturbances. In a case-control study, an association between homozygous A/A as well as homozygous G/G carriers of SNP rs 4704397 in PDE8B and recurrent miscarriage was found. The explanation for this association is unknown. In a nationwide survey, all guidelines for thyroid testing and management of hypothyroidism during pregnancy in Sweden were collected and compared with international guidelines. The local guidelines were variable and poorly compliant with the international guidelines. In a follow-up in one district, 5,254 pregnant women were included for subsequent review of their medical reports. We found a targeted thyroid testing rate of 20.1% in clinical practice, with an overall frequency of women with trimester-specific elevated TSH of 18.5%. More disturbingly, half of the women who were on levothyroxine treatment at the time of conception had an elevated TSH level at thyroid testing. In a subsequent cohort study of the 5,254 women, we found the prevalence of trimester-specific elevated TSH and overt hypothyroidism to be equal in targeted thyroid tested and untested women. In a cross-sectional study, a median urinary iodine concentration (UIC) of 98 μg/l was found in the study population. According to WHO/UNICEF/IGN criteria, the population-based median UIC during pregnancy should be 150-249 μg/l. In conclusion, genetic variations may contribute to adverse pregnancy outcomes. In clinical practice, thyroid testing and the management of hypothyroidism during pregnancy is unsatisfactory, regarding the whole chain from development of local guidelines to their implementation and to targeted thyroid testing. Moreover, our results indicate insufficient iodine status in the pregnant population of Sweden.

Conselho Nacional de Desenvolvimento Científico e Tecnológico / Hypothyroidism is a syndrome resulting from decreased production and secretion of triiothyronine (T3) and thyroxine (T4) hormones, frequently diagnosed in women. Clinical and experimental evidence support the association between reduction in thyroid hormones, neuropsychiatric disorders and oxidative stress. Selenium (Se) is a trace element essential to thyroid functions. The present study investigated the effect of diphenyl diselenide supplementation in a model of methimazole-induced hypothyroidism in female rats. We evaluated behavioral parameters related to memory and spatial learning (Article 1) and depressive-like behavior (Manuscript 1). Biochemical parameters were also investigated in relation to oxidative stress, MAO activity and the expression of antioxidant enzymes genes (Manuscripts 1 and 2). In Article 1, we observed a significant effect of diet supplemented with diphenyl diselenide in improving memory and spatial learning deficits in hypothyroid animals undergoing the task of Morris Water Maze. In Manuscript 1 we observed that methimazole-induced hypothyroidism caused a depressive-like behavior assessed in the forced swimming test and that supplementation with diphenyl diselenide caused a reversal of this effect. Furthermore, animals supplemented with diphenyl diselenide performed better in evaluating the antidepressant-like effect. In both (Article 1 and Manuscript 1), there were no motor and/or anxiety alterations, which could interfere with the results. Biochemical parameters in Manuscript 1 and 2 demonstrated that diphenyl diselenide improved analyzes related to oxidative stress (TBARS, ROS and NP-SH) in brain structures and restored the activity of MAO-B (Manuscript 1). In addition, Manuscript 2 evaluated the effects of hypothyroidism and supplementation with diphenyl diselenide on gene expression of antioxidant enzymes and transcription factor NRF-2. The results showed that hypothyroidism caused a significant increase in the expression of antioxidant enzymes, positively correlated to the transcription factor NRF-2. This effect was observed predominantly in the cerebral cortex and hippocampus, whereas supplementation with diphenyl diselenide was effective in normalizing the levels of antioxidant gene expression. Although hypothyroidism has caused a significant increase in gene expression levels of SOD, CAT and GPx were not observed changes in enzyme activity. Finally, the results of this study indicate through different experimental protocols that methimazole-induced hypothyroidism caused a deficit in spatial learning and memory, and depressive-like behavior. In addition, there were changes related to oxidative stress and the regulation of gene expression related to the antioxidant defense system. Diphenyl diselenide presented significant effects in promoting the reversal of behavioral effects and restore the biochemical parameters, and its role in regulating the expression of genes related to antioxidant defense system, adding a new interpretation to its pharmacological effects and demonstrates its potential to treat the complications caused by hypothyroidism. / O hipotireoidismo é uma síndrome caracterizada pela produção e secreção insuficiente dos hormônios tireóideos, triiodotironina (T3) e tiroxina (T4), frequentemente diagnosticada em mulheres. Evidências clínicas e experimentais têm relatado a associação entre redução dos hormônios tireóideos, doenças neuropsiquiátricas e estresse oxidativo. O selênio (Se) é um elemento traço essencial às funções tireóideas. Este estudo investigou o efeito da suplementação com disseleneto de difenila sobre parâmetros comportamentais e bioquímicos em um modelo de indução ao hipotireoidismo pelo metimazol, em ratas. Foram avaliados parâmetros comportamentais relacionados à memória e à aprendizagem espacial (Artigo 1) e ao comportamento semelhante à depressão (Manuscrito 1). Parâmetros bioquímicos também foram investigados em relação ao estresse oxidativo, à atividade da enzima MAO e à expressão gênica relacionada ao sistema de defesa antioxidante (Manuscritos 1 e 2). No Artigo 1, observamos um efeito significativo da dieta suplementada com disseleneto de difenila, ao reverter o déficit relacionando à memória e à aprendizagem espacial nos animais hipotireóideos submetidos à tarefa do Labirinto Aquático de Morris. No Manuscrito 1 observamos que o hipotireoidismo induzido pelo metimazol causou um comportamento semelhante à depressão avaliada no Teste do Nado Forçado e que a suplementação com disseleneto de difenila provocou a reversão desse efeito. Além disso, os animais suplementados com o disseleneto de difenila apresentaram um desempenho melhor na avaliação do efeito semelhante ao antidepressivo. Em ambos (Artigo 1 e Manuscrito 1), não ocorreram alterações motoras e/ou relacionadas à ansiedade, que pudessem interferir nos resultados. Os parâmetros bioquímicos avaliados nos Manuscritos 1 e 2 mostraram que o disseleneto de difenila melhorou os marcadores de estresse oxidativo (TBARS, ROS e NP-SH) nas estruturas cerebrais e restaurou a atividade da enzima MAO B (Manuscrito 1). Além disso, o Manuscrito 2 avaliou os efeitos do hipotireoidismo e da suplementação com disseleneto de difenila sobre a expressão gênica das enzimas antioxidantes e do fator de transcrição NRF-2. Os resultados mostraram que o hipotireoidismo provocou um aumento significativo na expressão das enzimas antioxidantes, correlacionado positivamente ao fator de transcrição NRF-2. Esse efeito foi predominantemente observado no córtex cerebral e no hipocampo, sendo que a suplementação com disseleneto de difenila foi efetiva em normalizar os níveis de expressão gênica antioxidante. Apesar de o hipotireoidismo ter causado um aumento significativo nos níveis de expressão gênica das enzimas SOD, CAT e GPx não se observaram alterações nas atividades enzimáticas. A partir desse estudo pode-se concluir através dos diferentes protocolos experimentais realizados que o hipotireoidismo induzido pelo metimazol causou déficit de memória e de aprendizagem espacial, bem como o comportamento semelhante à depressão. Além disso, observaram-se as alterações relacionadas ao estresse oxidativo e à regulação da expressão gênica relacionada ao sistema de defesa antioxidante. O disseleneto de difenila apresentou efeitos significativos na reversão dos efeitos comportamentais e na restauração dos parâmetros bioquímicos avaliados, sendo que a regulação da expressão de genes relacionados ao sistema de defesa antioxidante acrescenta uma nova interpretação aos seus efeitos farmacológicos e demonstra o seu potencial para tratar as complicações causadas pelo hipotireoidismo.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Changes in maternal thyroid hormones concentrations during pregnancy can affect the body development of pups. However, despite the recent race for the understanding of the mechanisms that explain the impact of perinatal life in the occurrence of different diseases, little has been done to investigate the role of maternal thyroid hormones for proper development of CNS structures, important in regulating perception nociceptive. In this sense, in the present study we investigate the effect of experimental gestational hypothyroidism (EGH) in biological systems of nociceptive circuitry. The EGH was induced by methimazole to 0.02% in drinking water from ninth day of gestation until delivery. The threshold for noxious temperature was evaluated by using the hot plate apparatus (52 ± 0.2 ° C) in male offspring from methimazole treated dams (OMTD) and offspring from water treated dams (OWTD), on postnatal day (PND) 60 days, in baseline condiction and after a drug injection (morphine, memantine, sertraline and AMPT). In addition, thyroid status was evaluated through the determination of total T3 and T4 serum levels on PND 60, sections through the vlPAG were processed for TH immunofluorescence, the contents of glutamate in the cerebrospinal fluid was measured and evaluated oxidative parameters in spinal cord. The results were expressed mean ± Standard Error values. Three and two way ANOVA, Student t test, Mann-Whitney and correlation test were used. The threshold of statistical significance was set at p<0.05. Thus, our data showed that EGH does not generate significant impact on the treated mothers when they are compared to control, but in the offspring important effects of lack of maternal THs in the intrauterine period were observed. OMTD had less body weight after 60 DPN (p <0.01), higher serum concentration of TT3 (p <0.05), higher analgesia on the hot plate after i.p. morphine, at times 30 and 60 minutes (time factor interaction and treatment (F (4, 80) = 2.50, p <0.05) and increased lipid peroxidation (assessed by quantification of TBARS) in the spinal cord (p <0.01 ). Given the above, we conclude that the lack of THs during pregnancy causes changes in body weight and serum concentrations of T3, as well as in biological systems of nociceptive circuitry. / Alterações das concentrações de hormônios tireoideanos maternos durante a gestação podem afetar o adequado desenvolvimento dos filhotes. No entanto, apesar da corrida recente pela compreensão dos mecanismos que expliquem as repercussões da vida perinatal na ocorrência de distintas doenças, pouco se tem feito para investigar o papel dos hormônios tireoideanos maternos para o adequado desenvolvimento das estruturas do SNC, importantes na regulação da percepção nociceptiva. Nesse sentido, no presente estudo, procurou-se investigar as repercussões do hipotireoidismo gestacional (HGE) materno nos sistemas biológicos centrais de controle nociceptivo. O HGE foi induzido adicionando metimazol a 0,02% na água de beber a partir do nono dia de gestação até o parto. Os machos da prole de mães hipotireoideas (PMH) e eutireoideas (PME) foram submetidos à avaliação basal e após a injeção de drogas (morfina, memantina, sertralina e AMPT), do limiar nociceptivo com 60 dias pós-natal (DPN) por meio do aparato da placa quente (52±0,2 C). Ademais, foi realizada a dosagem da triiodotironina e tiroxina totais (TT3 e TT4, respectivamente) séricos, quantificação de neurônios da substância cinzenta periaquedutal porção ventrolateral (PAGvl) imunomarcados para tirosina hidroxilase, quantificação de glutamato no líquor, além da avaliação de parâmetros oxidativos. Os resultados obtidos foram expressos em valores de média ± erro padrão da média. Para comparação dos dados entre os grupos foi realizado ANOVA three e two-way de medidas repetidas, student t test, Mann-withney e ANCOVA com distância percorrida como co-. O nível crítico fixado foi de 5% (P<0,05). Após análise dos dados foi possível observar que a PMH apresenta menor massa corporal aos 60 DPN (p<0.01), maior concentração sérica de TT3 (p<0.05), maior analgesia na placa quente após a administração i.p. de morfina nos tempos 30 e 60 minutos (fator interação tempo e tratamento (F(4, 80) = 2,50; p <0,05) e maior peroxidação lipídica (avaliada pela quantificação do TBARS) na medula espinhal (p<0.01) quando comparada ao grupo controle. Diante do exposto, concluímos que o HGE não gera repercussões importantes nas mães tratadas, quando estas são comparadas as controle, no entanto, a prole sofre importantes efeitos da carência dos hormônios tireoideanos maternos no período intraútero. A carência de HTs no período gestacional acarreta alterações no peso corporal e nas concentrações séricas de TT3, bem como nos sistemas biológicos de controle nociceptivo.

Introdução: As disfunções tireoidianas subclínicas são comuns na prática clínica, particularmente entre mulheres de meia idade. Existem algumas evidências de que as disfunções tireoidianas subclínicas podem afetar o risco cardiovascular de forma negativa, além de afetar a qualidade de vida e produzir sintomas somáticos e psicológicos. Entretanto ainda existe muita controvérsia sobre se o tratamento destas disfunções afeta positivamente algum desfecho clínico e se estaria indicado realizar um rastreamento populacional destas disfunções. Objetivo: Este estudo teve como objetivo determinar a freqüência das disfunções tireoidianas subclínicas e sua associação com fatores de risco cardiovasculares tradicionais e com alguns fatores psico-sociais em mulheres com 40 anos ou mais em seu local de trabalho. Métodos: Estudo transversal de rastreamento com funcionárias da Universidade de São Paulo com 40 anos ou mais. Todas as participantes foram entrevistadas e responderam a quatro questionários específicos validados [um questionário sobre características sócio-demográficas, o questionário de angina de Rose, o Short Form Health Survey - 36 (SF-36) e o Self-Report Questionnaire (SRQ-20)], foram submetidas a mensuração de medidas antropométricas e da pressão arterial e tiveram uma amostra de sangue colhida para avaliação de função tireoidiana (TSH e T4-livre) e anticorpos antitireoperoxidase (anti-TPO), glicemia de jejum e colesterol total, LDL-colesterol e HDL-colesterol. Em uma subamostra do estudo também foi dosada a proteína C ultra-sensível (hsCPR). As mulheres foram analisadas de acordo com seu estado funcional tireoidiano. Resultados: Das 736 funcionárias com 40 anos ou mais convidadas a participar, 314 (42,7%) aceitaram o convite. As freqüências de hipotireoidismo e hipertireoidismo subclínico foram, respectivamente, 7,3% e 5,1%. Anticorpos anti-tireoperoxidase positivos foram encontrados em 51 mulheres (16,2%). Níveis de TSH < 10 mIU/l estavam presentes em 78,3% das mulheres com hipotireoidismo subclínico. Não houve diferença nas características gerais, nos fatores de risco para doença cardiovascular, nos fatores psico-sociais nem, de uma forma geral, na qualidade de vida comparando-se as mulheres de acordo com sua função tireoidiana. Conclusão: Não se encontrou nenhuma associação entre disfunção tireoidiana subclínica e fatores de risco para doença cardiovascular. Não se encontrou nenhuma associação de disfunção tireoidiana subclínica e fatores psico-sociais (qualidade de vida, sintomas somáticos e psicológicos). Os resultados deste estudo transversal não suportam a prática de rastreamento rotineiro de disfunção tireoidiana subclínica. / Rational: Subclinical thyroid dysfunction is very common in clinical practice, particularly among middle-aged women. There is some evidence that subclinical thyroid dysfunction may affect cardiovascular risk in a negative fashion, and also affect quality of life and produce somatic and psychological symptoms. There remains much controversy as whether there should be a population based screening for these dysfunctions and whether treatment of these dysfunctions have any positive impact on clinical outcomes. Objective: The aim of this study was to determine the approximate frequency of subclinical thyroid dysfunction and its association with traditional cardiovascular risk factors as well as some psychosocial factors in women 40 years of age or older at the worksite. Methods: Cross-sectional screening study with women 40 years of age or older, working at the University of São Paulo. All the women answered four specific questionnaires [a questionnaire on socio-demographic characteristics, the Rose Angina Questionnaire, the Short Form Health Survey -36 (SF-36) and the Self- Report Questionnaire (SRQ-20)], had antropometric variables and blood pressure measured, and blood analyzed for total-cholesterol, LDL-cholesterol, HDL-cholesterol, tryglicerides, fasting glucose, thyroid-stimulating hormone (TSH), free-thyroxine (free-T4) and anti-thyreoperoxidase antibodies (anti-TPO). In a sub-sample of these women high-sensitive C reactive protein (hsCRP) was measured. Women were analyzed according to their thyroid function status. Results: Of the 736 women invited to participate, 314 (42.7%) accepted the invitation. The frequencies of subclinical hypothyroidism and subclinical hyperthyroidism were, respectively, 7.3% and 5.1%. Positive antibodies against thyreoperoxidase were present in 51 women (16.2%). TSH levels < 10 mIU/l were present in 78.3% of women with subclinical hypothyroidism. There was no difference in general characteristics, cardiovascular risk factors, psychosocial factors nor, in a general way, in quality of life among these women according to their thyroid function status. Conclusion: No association between cardiovascular risk factors and subclinical thyroid dysfunction was found. No association between subclinical thyroid dysfunction and psychosocial factors (quality of life, somatic and psychological symptoms) was found either. The results of this cross-section study do not support the routine screening of subclinical thyroid dysfunction.

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Changes in maternal thyroid hormones concentrations during pregnancy can affect the body development of pups. However, despite the recent race for the understanding of the mechanisms that explain the impact of perinatal life in the occurrence of different diseases, little has been done to investigate the role of maternal thyroid hormones for proper development of CNS structures, important in regulating perception nociceptive. In this sense, in the present study we investigate the effect of experimental gestational hypothyroidism (EGH) in biological systems of nociceptive circuitry. The EGH was induced by methimazole to 0.02% in drinking water from ninth day of gestation until delivery. The threshold for noxious temperature was evaluated by using the hot plate apparatus (52 ± 0.2 ° C) in male offspring from methimazole treated dams (OMTD) and offspring from water treated dams (OWTD), on postnatal day (PND) 60 days, in baseline condiction and after a drug injection (morphine, memantine, sertraline and AMPT). In addition, thyroid status was evaluated through the determination of total T3 and T4 serum levels on PND 60, sections through the vlPAG were processed for TH immunofluorescence, the contents of glutamate in the cerebrospinal fluid was measured and evaluated oxidative parameters in spinal cord. The results were expressed mean ± Standard Error values. Three and two way ANOVA, Student t test, Mann-Whitney and correlation test were used. The threshold of statistical significance was set at p<0.05. Thus, our data showed that EGH does not generate significant impact on the treated mothers when they are compared to control, but in the offspring important effects of lack of maternal THs in the intrauterine period were observed. OMTD had less body weight after 60 DPN (p <0.01), higher serum concentration of TT3 (p <0.05), higher analgesia on the hot plate after i.p. morphine, at times 30 and 60 minutes (time factor interaction and treatment (F (4, 80) = 2.50, p <0.05) and increased lipid peroxidation (assessed by quantification of TBARS) in the spinal cord (p <0.01 ). Given the above, we conclude that the lack of THs during pregnancy causes changes in body weight and serum concentrations of T3, as well as in biological systems of nociceptive circuitry. / Alterações das concentrações de hormônios tireoideanos maternos durante a gestação podem afetar o adequado desenvolvimento dos filhotes. No entanto, apesar da corrida recente pela compreensão dos mecanismos que expliquem as repercussões da vida perinatal na ocorrência de distintas doenças, pouco se tem feito para investigar o papel dos hormônios tireoideanos maternos para o adequado desenvolvimento das estruturas do SNC, importantes na regulação da percepção nociceptiva. Nesse sentido, no presente estudo, procurou-se investigar as repercussões do hipotireoidismo gestacional (HGE) materno nos sistemas biológicos centrais de controle nociceptivo. O HGE foi induzido adicionando metimazol a 0,02% na água de beber a partir do nono dia de gestação até o parto. Os machos da prole de mães hipotireoideas (PMH) e eutireoideas (PME) foram submetidos à avaliação basal e após a injeção de drogas (morfina, memantina, sertralina e AMPT), do limiar nociceptivo com 60 dias pós-natal (DPN) por meio do aparato da placa quente (52±0,2 C). Ademais, foi realizada a dosagem da triiodotironina e tiroxina totais (TT3 e TT4, respectivamente) séricos, quantificação de neurônios da substância cinzenta periaquedutal porção ventrolateral (PAGvl) imunomarcados para tirosina hidroxilase, quantificação de glutamato no líquor, além da avaliação de parâmetros oxidativos. Os resultados obtidos foram expressos em valores de média ± erro padrão da média. Para comparação dos dados entre os grupos foi realizado ANOVA three e two-way de medidas repetidas, student t test, Mann-withney e ANCOVA com distância percorrida como co-. O nível crítico fixado foi de 5% (P<0,05). Após análise dos dados foi possível observar que a PMH apresenta menor massa corporal aos 60 DPN (p<0.01), maior concentração sérica de TT3 (p<0.05), maior analgesia na placa quente após a administração i.p. de morfina nos tempos 30 e 60 minutos (fator interação tempo e tratamento (F(4, 80) = 2,50; p <0,05) e maior peroxidação lipídica (avaliada pela quantificação do TBARS) na medula espinhal (p<0.01) quando comparada ao grupo controle. Diante do exposto, concluímos que o HGE não gera repercussões importantes nas mães tratadas, quando estas são comparadas as controle, no entanto, a prole sofre importantes efeitos da carência dos hormônios tireoideanos maternos no período intraútero. A carência de HTs no período gestacional acarreta alterações no peso corporal e nas concentrações séricas de TT3, bem como nos sistemas biológicos de controle nociceptivo.