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1.
J Clin Endocrinol Metab ; 103(11): 3986-3992, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30137405

RESUMO

Context: Despite apparent muscle weakness in overt or even subclinical hyperthyroidism, the effects of thyroid function in the reference range on muscle strength are unknown. Objective: To investigate the association of serum TSH and free T4 with handgrip strength (HGS) in euthyroid elderly. Design and Setting: A nationally representative population-based, cross-sectional study from the Korea National Health and Nutrition Examination Surveys. Participants: A total of 650 men aged ≥50 years and 533 postmenopausal women. Main Outcome Measures: HGS was measured using a digital grip strength dynamometer, and low muscle strength was defined based on the Korean specific cutoff point of HGS (28.9 and 16.8 kg in men and women, respectively). Results: After adjustment for confounders, lower serum TSH but not free T4 was associated with lower HGS in men (P = 0.032). Compared with men with high-normal TSH, those with low-normal TSH consistently showed 5.0% lower HGS (P = 0.027), with a linear decrease in HGS across decreasing serum TSH quartiles (P for trend = 0.018). Men with low muscle strength had 22.0% lower serum TSH than those without (P = 0.015), and the odds for the risk of low muscle strength was 3.76 times higher among men with low-normal TSH than it was among those with high-normal TSH (P = 0.021). However, these associations were not observed in postmenopausal women. Conclusions: These results suggest that serum TSH level at the lower end of reference range may be associated with low muscle strength, especially in older men.


Assuntos
Força da Mão/fisiologia , Testes de Função Tireóidea/normas , Glândula Tireoide/fisiologia , Tireotropina/sangue , Adulto , Fatores Etários , Idoso , Estudos Transversais , Feminino , Humanos , Vida Independente/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Dinamômetro de Força Muscular , Inquéritos Nutricionais/estatística & dados numéricos , Pós-Menopausa/sangue , Pós-Menopausa/fisiologia , Valores de Referência , República da Coreia , Fatores Sexuais , Tireotropina/fisiologia , Tiroxina/sangue , Tiroxina/fisiologia
2.
J Clin Endocrinol Metab ; 103(11): 4125-4134, 2018 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-30020476

RESUMO

Context: Although the skeleton is a well-known thyroid hormone target organ, very little data are available on the association of thyroid function with bone outcomes during childhood. Objective: To study the association of thyroid function with bone mass during childhood. Design, Setting, and Participants: Population-based prospective cohort including 4204 children with TSH and free T4 (FT4) measured at the age of 6 years. Main Outcome Measures: Bone density was assessed by a total body dual-energy X-ray absorptiometry scan at the median age of 6 years (95% range, 5.6 to 7.9) and at the age of 10 years (95% range, 9.0 to 10.9) in 4204 and 3404 participants, respectively. Results: There was an inverse association of TSH with bone mineral density (BMD) at the age of 6 (ß -0.028 ± 0.011, P = 0.009) and with follow-up measurements at the age of 10 (ß -0.027 ± 0.011, P = 0.014), but not with bone mineral content (BMC) at the age of 6 (ß -0.028 ± 0.015, P = 0.06) or for follow-up measurements of BMC at the age of 10 (ß -0.011 ± 0.015, P = 0.47). There was an inverse association of FT4 with BMD (ß -0.016 ± 0.006, P = 0.014) and BMC (ß -0.023 ± 0.009, P = 0.009) cross-sectionally, and also at the age of 10 years (BMD: ß -0.018 ± 0.007, P = 0.007; BMC: ß -0.021 ± 0.009, P = 0.020). Conclusion: A higher FT4 concentration is associated with lower bone mass at the age of 6 and at the age of 10 years. These data provide insights into the effects of thyroid function on bone physiology during childhood.


Assuntos
Densidade Óssea/fisiologia , Desenvolvimento Infantil/fisiologia , Glândula Tireoide/fisiologia , Tiroxina/sangue , Absorciometria de Fóton , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/fisiologia , Criança , Feminino , Seguimentos , Humanos , Masculino , Países Baixos , Estudos Prospectivos , Testes de Função Tireóidea/métodos , Tiroxina/fisiologia
3.
J Clin Endocrinol Metab ; 103(4): 1291-1295, 2018 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-29409047

RESUMO

Context: The nonthyroidal illness syndrome (NTIS) is a constellation of changes in circulating thyroid hormone levels that occur in euthyroid patients with acute or chronic systemic diseases. The changes that occur include a reduction in serum T3, an increase in serum rT3, and variable changes in circulating T4 levels. No consensus exists regarding therapeutic intervention for NTIS. Methods: We briefly review the published literature on the physiological actions of T4 and of rT3-hormones that until recently have been seen to have little or no bioactivity-and analyze the apparent significance of changes in circulating T4 and T3 encountered in the setting of NTIS in patients with cancer. In the case of T4, these actions may be initiated at a cancer or endothelial cell plasma membrane receptor on integrin αvß3 or at the cytoskeleton. Results: This review examines possible therapeutic intervention in NTIS in patients with cancer in terms of T4 reduction and T3 support. Evidence also exists that rT3 may support cancer. Conclusions: Prospective study is proposed of pharmacological reduction of normal or elevated T4 in cancer-associated NTIS. We also support investigation of normally circulating levels of T3 in such patients.


Assuntos
Síndromes do Eutireóideo Doente/sangue , Integrina alfaVbeta3/fisiologia , Tiroxina/fisiologia , Tri-Iodotironina/fisiologia , Síndromes do Eutireóideo Doente/etiologia , Humanos , Neoplasias/sangue , Neoplasias/complicações , Síndromes Paraneoplásicas/sangue , Síndromes Paraneoplásicas/etiologia , Tiroxina/sangue , Tri-Iodotironina/sangue
4.
J Comp Physiol B ; 187(5-6): 857-868, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28365894

RESUMO

Thyroid hormones play an important role in regulating seasonal adaptations of mammals. Several studies suggested that reduced availability of 3,3',5-triiodothyronine (T3) in the hypothalamus is required for the physiological adaptation to winter in Djungarian hamsters. We have previously shown that T3 is involved in the regulation of daily torpor, but it remains unclear, whether T3 affects torpor by central or peripheral mechanisms. To determine the effect of T3 concentrations within the hypothalamus in regulating daily torpor, we tested the hypothesis that low hypothalamic T3 metabolism would favour torpor and high T3 concentrations would not. In experiment 1 gene expression in torpid hamsters was assessed for transporters carrying thyroid hormones between cerebrospinal fluid and hypothalamic cells and for deiodinases enzymes, activating or inactivating T3 within hypothalamic cells. Gene expression analysis suggests reduced T3 in hypothalamic cells during torpor. In experiment 2, hypothalamic T3 concentrations were altered via microdialysis and torpor behaviour was continuously monitored by implanted body temperature transmitters. Increased T3 concentrations in the hypothalamus reduced expression of torpor as well as torpor bout duration and depth. Subsequent analysis of gene expression in the ependymal layer of the third ventricle showed clear up-regulation of T3 inactivating deiodinase 3 but no changes in several other genes related to photoperiodic adaptations in hamsters. Finally, serum analysis revealed that increased total T3 serum concentrations were not necessary to inhibit torpor expression. Taken together, our results are consistent with the hypothesis that T3 availability within the hypothalamus significantly contributes to the regulation of daily torpor via a central pathway.


Assuntos
Hipotálamo/fisiologia , Phodopus/genética , Phodopus/fisiologia , Torpor/fisiologia , Tri-Iodotironina/fisiologia , Animais , Regulação da Expressão Gênica , Masculino , Microdiálise , Tiroxina/sangue , Tiroxina/fisiologia , Tri-Iodotironina/sangue
5.
J Endocrinol ; 233(3): 209-216, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28348112

RESUMO

The endocrine body rhythms including the hypothalamic-pituitary-thyroid axis seem to be regulated by the circadian timing system, and daily rhythmicity of circulating thyroid-stimulating hormone (TSH) is well established. The circadian rhythms are generated by endogenous clocks in the central brain oscillator located in the hypothalamic suprachiasmatic nucleus (SCN) as well as multiple peripheral clocks, but information on the existence and function of a thyroid clock is limited. The molecular machinery in all clock cells is composed of a number of clock genes and their gene products are connected by autoregulatory feedback loops. Here, we provide evidence for a thyroid clock in the rat by demonstrating 24-h antiphase oscillations for the mRNA of the canonical clock genes Per1 and Bmal1, which was unaffected by hypophysectomy. By immunostaining, we supported the existence of a core oscillator in the individual thyroid cells by demonstrating a daily cytoplasmatic-nuclear shuttling of PER1 protein. In normal rats, we found a significant daily rhythmicity in the circulating thyroid hormones preceded by a peak in TSH. In hypophysectomised rats, although the thyroid clock was not affected, the oscillations in circulating thyroid hormones were abolished and the levels were markedly lowered. No daily oscillations in the expression of TSH receptor mRNA were observed in neither control rats nor hypophysectomised rats. Our findings indicate that the daily rhythm of thyroid hormone secretion is governed by SCN signalling via the rhythmic TSH secretion rather than by the local thyroid clock, which was still ticking after hypophysectomy.


Assuntos
Relógios Biológicos/fisiologia , Hipofisectomia/métodos , Glândula Tireoide/fisiologia , Tiroxina/fisiologia , Tri-Iodotironina/fisiologia , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Animais , Feminino , Regulação da Expressão Gênica/fisiologia , Masculino , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos
6.
Sleep Med ; 23: 21-25, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27692273

RESUMO

OBJECTIVE: In obstructive sleep apnea (OSA), while both hypothyroidism and hyperthyroidism have been studied, the occurrence of non-thyroidal illness syndrome (NTIS) (normal thyroid stimulating hormone [TSH] with low triiodotironine) has not been investigated. We explored the occurrence of NTIS in patients with moderate to severe OSA and its relationship to the severity of nocturnal respiratory disorders. We also studied the occurrence of subclinical hypothyroidism (SH, ie, high TSH with normal thyroxine) in OSA and changes in circulating TSH, free triiodotironine (fT3) and free thyroxine (fT4) after CPAP treatment. METHODS: After a nocturnal respiratory polysomnography, 125 consecutive patients with moderate to severe OSA and 60 control subjects with normal nocturnal respiration were recruited. Morning circulating TSH, fT3, and fT4 were measured in all subjects. In a subsample of patients, nocturnal polysomnography and hormonal determinations were repeated after CPAP treatment for five months. RESULTS: NTIS was found in 13 (10.4%), and SH in ten (8%) OSA subjects, but not in any control subjects. Patients with NTIS showed worse mean nocturnal oxygen saturation and time with saturation <90% (both p < 0.001). After treatment, NTIS subjects (n = 13) showed an increase in fT3 (p < 0.001) to the normal range, and SH subjects (n = 6) a slight decrease in TSH (p = 0.01). In the patients with normal hormones before treatment (n = 45), no change was observed. CONCLUSIONS: NTIS may occur in OSA patients with severe nocturnal hypoxemia. OSA treatment is followed by an improvement in TSH in patients with abnormal baseline levels of this hormone, and by recovery of NTIS.


Assuntos
Pressão Positiva Contínua nas Vias Aéreas , Síndromes do Eutireóideo Doente/fisiopatologia , Apneia Obstrutiva do Sono/fisiopatologia , Hormônios Tireóideos/sangue , Estudos de Casos e Controles , Síndromes do Eutireóideo Doente/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Polissonografia , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/terapia , Hormônios Tireóideos/fisiologia , Tiroxina/sangue , Tiroxina/fisiologia , Tri-Iodotironina/sangue , Tri-Iodotironina/fisiologia
7.
Cornea ; 35(10): 1338-46, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27560028

RESUMO

PURPOSE: Keratoconus (KC) is a corneal ectasia whose pathophysiology is still mostly unknown. We investigated whether thyroid gland dysfunction (TGD) is associated with the development of KC. METHODS: We first conducted an epidemiological study, examining the prevalence of TGD among patients with KC. Then, we compared tear thyroxine (T4) in TGD and immunohistochemical staining of its receptors (T4Rs) between patients with KC and controls. The significance of T4 for corneal metabolism was studied in organotypic tissue cultures from monkey corneas. RESULTS: We found that TGD prevalence among patients with KC is 13.6%, which is higher than its prevalence in the general population (about 2%). Tear T4 was higher in KC, and keratocyte T4Rs were elevated in KC compared with controls. Furthermore, core proteins such as collagen and cytokeratins were equally altered both in KC and in the cultured corneas substituted with T4. CONCLUSIONS: Our data implicate a crucial role of T4 in KC pathophysiology, which is most likely mediated by T4Rs.


Assuntos
Ceratocone/fisiopatologia , Doenças da Glândula Tireoide/fisiopatologia , Tiroxina/fisiologia , Adulto , Idoso , Animais , Técnicas de Cultura de Células , Ceratócitos da Córnea/metabolismo , Ensaio de Imunoadsorção Enzimática , Estudos Epidemiológicos , Proteínas do Olho/metabolismo , Feminino , Humanos , Imuno-Histoquímica , Ceratocone/epidemiologia , Ceratocone/metabolismo , Ceratoplastia Penetrante , Macaca fascicularis , Masculino , Pessoa de Meia-Idade , Prevalência , Receptores dos Hormônios Tireóideos/metabolismo , Lágrimas/metabolismo , Doenças da Glândula Tireoide/epidemiologia , Doenças da Glândula Tireoide/metabolismo , Tireotropina/metabolismo , Adulto Jovem
8.
Lancet Diabetes Endocrinol ; 4(1): 35-43, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26497402

RESUMO

BACKGROUND: Thyroid hormone is involved in the regulation of early brain development. Since the fetal thyroid gland is not fully functional until week 18-20 of pregnancy, neuronal migration and other crucial early stages of intrauterine brain development largely depend on the supply of maternal thyroid hormone. Current clinical practice mostly focuses on preventing the negative consequences of low thyroid hormone concentrations, but data from animal studies have shown that both low and high concentrations of thyroid hormone have negative effects on offspring brain development. We aimed to investigate the association of maternal thyroid function with child intelligence quotient (IQ) and brain morphology. METHODS: In this population-based prospective cohort study, embedded within the Generation R Study (Rotterdam, Netherlands), we investigated the association of maternal thyroid function with child IQ (assessed by non-verbal intelligence tests) and brain morphology (assessed on brain MRI scans). Eligible women were those living in the study area at their delivery date, which had to be between April 1, 2002, and Jan 1, 2006. For this study, women with available serum samples who presented in early pregnancy (<18 weeks) were included. Data for maternal thyroid-stimulating hormone, free thyroxine, thyroid peroxidase antibodies (at weeks 9-18 of pregnancy), and child IQ (assessed at a median of 6·0 years of age [95% range 5·6-7·9 years]) or brain MRI scans (done at a median of 8·0 years of age [6·2-10·0]) were obtained. Analyses were adjusted for potential confounders including concentrations of human chorionic gonadotropin and child thyroid-stimulating hormone and free thyroxine. FINDINGS: Data for child IQ were available for 3839 mother-child pairs, and MRI scans were available from 646 children. Maternal free thyroxine concentrations showed an inverted U-shaped association with child IQ (p=0·0044), child grey matter volume (p=0·0062), and cortex volume (p=0·0011). For both low and high maternal free thyroxine concentrations, this association corresponded to a 1·4-3·8 points reduction in mean child IQ. Maternal thyroid-stimulating hormone was not associated with child IQ or brain morphology. All associations remained similar after the exclusion of women with overt hypothyroidism and overt hyperthyroidism, and after adjustment for concentrations of human chorionic gonadotropin, child thyroid-stimulating hormone and free thyroxine or thyroid peroxidase antibodies (continuous or positivity). INTERPRETATION: Both low and high maternal free thyroxine concentrations during pregnancy were associated with lower child IQ and lower grey matter and cortex volume. The association between high maternal free thyroxine and low child IQ suggests that levothyroxine therapy during pregnancy, which is often initiated in women with subclinical hypothyroidism during pregnancy, might carry the potential risk of adverse child neurodevelopment outcomes when the aim of treatment is to achieve high-normal thyroid function test results. FUNDING: The Netherlands Organisation for Health Research and Development (ZonMw) and the European Community's Seventh Framework Programme.


Assuntos
Encéfalo/anatomia & histologia , Inteligência/fisiologia , Troca Materno-Fetal , Glândula Tireoide/metabolismo , Anticorpos/sangue , Criança , Pré-Escolar , Feminino , Sangue Fetal/metabolismo , Idade Gestacional , Humanos , Iodeto Peroxidase/sangue , Iodeto Peroxidase/imunologia , Saúde Materna , Gravidez , Estudos Prospectivos , Tireotropina/sangue , Tiroxina/fisiologia
9.
Oncogene ; 35(15): 1977-87, 2016 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-26165836

RESUMO

Ovarian carcinoma is the fifth common cause of cancer death in women, despite advanced therapeutic approaches. αvß3 integrin, a plasma membrane receptor, binds thyroid hormones (L-thyroxine, T4; 3,5,3'-triiodo-L-thyronine, T3) and is overexpressed in ovarian cancer. We have demonstrated selective binding of fluorescently labeled hormones to αvß3-positive ovarian cancer cells but not to integrin-negative cells. Physiologically relevant T3 (1 nM) and T4 (100 nM) concentrations in OVCAR-3 (high αvß3) and A2780 (low αvß3) cells promoted αv and ß3 transcription in association with basal integrin levels. This transcription was effectively blocked by RGD (Arg-Gly-Asp) peptide and neutralizing αvß3 antibodies, excluding T3-induced ß3 messenger RNA, suggesting subspecialization of T3 and T4 binding to the integrin receptor pocket. We have provided support for extracellular regulated kinase (ERK)-mediated transcriptional regulation of the αv monomer by T3 and of ß3 monomer by both hormones and documented a rapid (30-120 min) and dose-dependent (0.1-1000 nM) ERK activation. OVCAR-3 cells and αvß3-deficient HEK293 cells treated with αvß3 blockers confirmed the requirement for an intact thyroid hormone-integrin interaction in ERK activation. In addition, novel data indicated that T4, but not T3, controls integrin's outside-in signaling by phosphorylating tyrosine 759 in the ß3 subunit. Both hormones induced cell proliferation (cell counts), survival (Annexin-PI), viability (WST-1) and significantly reduced the expression of genes that inhibit cell cycle (p21, p16), promote mitochondrial apoptosis (Nix, PUMA) and tumor suppression (GDF-15, IGFBP-6), particularly in cells with high integrin expression. At last, we have confirmed that hypothyroid environment attenuated ovarian cancer growth using a novel experimental platform that exploited paired euthyroid and severe hypothyroid serum samples from human subjects. To conclude, our data define a critical role for thyroid hormones as potent αvß3-ligands, driving ovarian cancer cell proliferation and suggest that disruption of this axis may present a novel treatment strategy in this aggressive disease.


Assuntos
Integrina alfaVbeta3/fisiologia , Sistema de Sinalização das MAP Quinases/fisiologia , Proteínas de Neoplasias/fisiologia , Neoplasias Hormônio-Dependentes/metabolismo , Neoplasias Ovarianas/metabolismo , Tiroxina/fisiologia , Tri-Iodotironina/fisiologia , Anticorpos Neutralizantes/farmacologia , Divisão Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Meios de Cultura/farmacologia , Ativação Enzimática , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hipotireoidismo/sangue , Integrina alfaV/genética , Integrina alfaV/metabolismo , Integrina alfaVbeta3/biossíntese , Integrina alfaVbeta3/genética , Integrina alfaVbeta3/imunologia , Integrina beta3/genética , Integrina beta3/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasias Hormônio-Dependentes/genética , Neoplasias Hormônio-Dependentes/patologia , Oligopeptídeos/farmacologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Fosforilação , Processamento de Proteína Pós-Traducional , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Tiroxina/sangue , Tiroxina/farmacologia , Transcrição Genética/efeitos dos fármacos , Transcrição Genética/fisiologia , Tri-Iodotironina/sangue , Tri-Iodotironina/farmacologia
10.
PLoS One ; 10(3): e0121878, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25822259

RESUMO

The human hair follicle (HF) exhibits peripheral clock activity, with knock-down of clock genes (BMAL1 and PER1) prolonging active hair growth (anagen) and increasing pigmentation. Similarly, thyroid hormones prolong anagen and stimulate pigmentation in cultured human HFs. In addition they are recognized as key regulators of the central clock that controls circadian rhythmicity. Therefore, we asked whether thyroxine (T4) also influences peripheral clock activity in the human HF. Over 24 hours we found a significant reduction in protein levels of BMAL1 and PER1, with their transcript levels also decreasing significantly. Furthermore, while all clock genes maintained their rhythmicity in both the control and T4 treated HFs, there was a significant reduction in the amplitude of BMAL1 and PER1 in T4 (100 nM) treated HFs. Accompanying this, cell-cycle progression marker Cyclin D1 was also assessed appearing to show an induced circadian rhythmicity by T4 however, this was not significant. Contrary to short term cultures, after 6 days, transcript and/or protein levels of all core clock genes (BMAL1, PER1, clock, CRY1, CRY2) were up-regulated in T4 treated HFs. BMAL1 and PER1 mRNA was also up-regulated in the HF bulge, the location of HF epithelial stem cells. Together this provides the first direct evidence that T4 modulates the expression of the peripheral molecular clock. Thus, patients with thyroid dysfunction may also show a disordered peripheral clock, which raises the possibility that short term, pulsatile treatment with T4 might permit one to modulate circadian activity in peripheral tissues as a target to treat clock-related disease.


Assuntos
Relógios Biológicos/fisiologia , Folículo Piloso/fisiologia , Tiroxina/fisiologia , Fatores de Transcrição ARNTL/genética , Fatores de Transcrição ARNTL/metabolismo , Relógios Biológicos/efeitos dos fármacos , Relógios Biológicos/genética , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Ciclina D1/genética , Ciclina D1/metabolismo , Folículo Piloso/efeitos dos fármacos , Humanos , Masculino , Técnicas de Cultura de Órgãos , Proteínas Circadianas Period/genética , Proteínas Circadianas Period/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tiroxina/farmacologia , Regulação para Cima/efeitos dos fármacos
11.
Alcohol Alcohol ; 50(1): 24-9, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25433251

RESUMO

AIMS: A few studies have suggested a relationship between thyroid hormones and alcohol dependence (AD) such as a blunted increase of thyroid stimulating hormone (TSH) in response to thyrotropin-releasing hormone (TRH), lower levels of circulating free triiodothyronine (fT3) and free thyroxine (fT4) levels and down regulation of the TRH receptors. The current study aimed to explore the relationship between the hormones of the thyroid axis and alcohol-seeking behaviors in a sample of alcohol-dependent patients. METHODS: Forty-two treatment-seeking alcohol-dependent individuals enrolled in a 12-week treatment study were considered. The Timeline Follow Back (TLFB) was used to assess the number of drinks consumed during the 12-week period. Blood levels of thyroid hormones (TSH, fT3 and fT4) were measured prior to and at the end of treatment. Questionnaires were administered to evaluate craving for alcohol [Penn Alcohol Craving Scale (PACS) and the Obsessive Compulsive Drinking Scale (OCDS) and its two subscales ODS for obsessions and CDS for compulsions] as well as anxiety [State and Trait Inventory (STAI)], depression [the Zung Self-Rating Depression Scale (Zung)] and aggression [the Aggressive Questionnaire (AQ)]. RESULTS: At baseline, we found significant positive correlations between fT3 and OCDS (r = 0.358, P = 0.029) and CDS (r = 0.405, P = 0.013) and negative correlations between TSH levels and STAI (r = -0.342, P = 0.031), and AQ (r = -0.35, P = 0.027). At the end of the 12-week study period, abstinent patients had a greater change in TSH than those who relapsed (-0.4 vs. -0.25, F(1,24) = 5.4, P = 0.029). CONCLUSION: If confirmed in larger samples, these findings could suggest that the thyroid axis might represent a biomarker of alcohol craving and drinking.


Assuntos
Consumo de Bebidas Alcoólicas/fisiopatologia , Fissura/fisiologia , Hormônios Tireóideos/fisiologia , Adolescente , Adulto , Abstinência de Álcool/estatística & dados numéricos , Consumo de Bebidas Alcoólicas/sangue , Consumo de Bebidas Alcoólicas/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Psicológicos , Inquéritos e Questionários , Hormônios Tireóideos/sangue , Tireotropina/sangue , Tireotropina/fisiologia , Tiroxina/sangue , Tiroxina/fisiologia , Tri-Iodotironina/sangue , Tri-Iodotironina/fisiologia , Adulto Jovem
12.
Mol Cell Biochem ; 399(1-2): 87-94, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25304215

RESUMO

Endothelial system acts as a large endocrine organ in the human body; however, little is still known about the regulative role of THs on endothelial cells. Aim of the present study was to investigate the expression of the TH deiodinases (D1, D2, and D3) and TH receptors (TRα1, TRα2, and TRß1) in an endothelial microvascular cultured cell model (HMEC-1), after stimulation with triiodothyronine (T3, 10-100 nM), thyroxine (T4, 10-100 nM), and reverse T3 (rT3, 1-10 nM). DIO1 was significantly inhibited by T4 at 10 and 100 nM (p < 0.001). rT3 significantly inhibited DIO1 at 1 nM concentration (p < 0.01) and stimulated DIO1 at 10 nM dosage (p < 0.001). T4 and rT3 significantly inhibited DIO2 at all concentrations. DIO3 was induced at 100 nM T3 (p < 0.05) and 100 nM rT3 (p < 0.01), and TRα1 and TRα2 mRNAs were significantly increased after 100 nM T3 treatment (p < 0.05) and decreased after 1 and 10 nM rT3 (p < 0.05). TRß1 was significantly increased by all THs at different concentrations: 10 nM T3 and 100 nM T3 (p < 0.05), 1 nM rT3 (p < 0.001), and 100 nM T4 (p < 0.01). D1 and D2 protein levels were evaluated, but no significant difference was observed for any hormonal treatment. For the first time, we found that the TH deiodinases and receptors are expressed in endothelial HMEC-1 cells. These findings might be of significant clinical relevance, given the important regulatory role of the endothelium as first barrier to the bloodstream.


Assuntos
Células Endoteliais/enzimologia , Endotélio Vascular/citologia , Iodeto Peroxidase/metabolismo , Linhagem Celular , Derme/irrigação sanguínea , Expressão Gênica , Humanos , Iodeto Peroxidase/genética , Microvasos/citologia , Receptores dos Hormônios Tireóideos/genética , Receptores dos Hormônios Tireóideos/metabolismo , Tiroxina/fisiologia , Tri-Iodotironina/fisiologia
13.
Am J Physiol Lung Cell Mol Physiol ; 308(3): L301-6, 2015 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-25480330

RESUMO

Hypothyroidism may reduce, whereas hyperthyroidism may aggravate, asthma symptoms. The mechanisms underlying this relationship are largely unknown. Since thyroid hormones have central roles in cell growth and differentiation, we hypothesized that airway remodeling, in particular increased airway smooth muscle (ASM) mass, may be involved. To address this hypothesis, we investigated the effects of triiodothyronine (T3) and l-thyroxine (T4) in the absence and presence of the profibrotic transforming growth factor (TGF)-ß1 on human ASM cell phenotype switching. T3 (1-100 nM) and T4 (1-100 nM) did not affect basal ASM proliferation. However, when combined with TGF-ß1 (2 ng/ml), T4 synergistically increased the proliferative response, whereas only a minor effect was observed for T3. In line with a switch from a contractile to a proliferative ASM phenotype, T4 reduced the TGF-ß1-induced contractile protein expression by ∼50%. Cotreatment with T3 reduced TGF-ß1-induced contractile protein expression by ∼25%. The synergistic increase in proliferation was almost fully inhibited by the integrin αvß3 antagonist tetrac (100 nM), whereas no significant effects of the thyroid receptor antagonist 1-850 (3 µM) were observed. Inhibition of MEK1/2, downstream of the integrin αvß3, also inhibited the T4- and TGF-ß1-induced proliferative responses. Collectively, the results indicate that T4, and to a lesser extent T3, promotes a proliferative ASM phenotype in the presence of TGF-ß1, which is predominantly mediated by the membrane-bound T4 receptor αvß3. These results indicate that thyroid hormones may enhance ASM remodeling in asthma, which could be of relevance for hyperthyroid patients with this disease.


Assuntos
Miócitos de Músculo Liso/fisiologia , Tiroxina/fisiologia , Fator de Crescimento Transformador beta1/fisiologia , Remodelação das Vias Aéreas , Brônquios/patologia , Linhagem Celular , Proliferação de Células , Regulação para Baixo , Expressão Gênica , Humanos , Integrina alfaVbeta3/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Fenótipo , Tri-Iodotironina/fisiologia
14.
Exp Gerontol ; 60: 173-82, 2014 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-25446982

RESUMO

Development of experimental models of life span regulation is an important goal of modern gerontology. We proposed a thyroxin model of accelerated aging. Male Wistar rats at the age of 17 months received thyroxin in drinking water at a concentration of 6 mg/L for 2 months as a model of induced hyperthyroidism (IH). Administration of thyroxin resulted in a decrease in life span and a 2°C increase in body temperature that was accompanied by a 2 fold increase in thyroxin level and a 40% increase in triiodothyronine in blood serum. Induced hyperthyroidism can be used as a model of accelerated aging. We also found that thyroxin administration acts as uncoupler of oxidative phosphorylation as treatment was accompanied by an increase in the generation of superoxide radicals by 50%. Antioxidant enzyme activity remained unchanged (glutathione peroxidase, glutathione reductase mitochondrial) or was reduced (glutathione-S-transferase by 1.7 times) as compared with the control. The activity of glucose-6-transferase was increased by 2.8 times as compared with control, and malate dehydrogenase activity in liver increased by 6.8 times. Induced hyperthyroidism in rats resulted in distinct epigenotype which was accompanied by a decrease in life span.


Assuntos
Envelhecimento/fisiologia , Longevidade/fisiologia , Termogênese/fisiologia , Tiroxina/fisiologia , Senilidade Prematura/sangue , Senilidade Prematura/etiologia , Senilidade Prematura/fisiopatologia , Animais , Antioxidantes/metabolismo , Modelos Animais de Doenças , Glutationa/metabolismo , Hipertireoidismo/sangue , Hipertireoidismo/complicações , Hipertireoidismo/fisiopatologia , Masculino , Mitocôndrias Hepáticas/metabolismo , Modelos Biológicos , Estresse Oxidativo , Ratos , Ratos Wistar , Tiroxina/sangue , Tri-Iodotironina/sangue
15.
J Vet Intern Med ; 28(4): 1301-9, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24934827

RESUMO

BACKGROUND: This study was performed to compare thyroid function of premature foals to term foals. HYPOTHESIS: Premature foals are more markedly hypothyroxinemic than expected for their severity of illness alone. ANIMALS: Twenty clinically normal term foals; 28 sick, hospitalized term foals; 24 sick, hospitalized premature foals. METHODS: Thyroid hormones (TH) and thyrotropin (TSH) were measured, both at rest and in response to thyrotropin-releasing hormone (TRH), in the 3 groups of foals. Clinical and clinicopathologic data were recorded. RESULTS: Normal foals had high TH at birth, which decreased over the first month into the normal reference range for adult horses. TSH was within the normal adult reference range soon after birth, and did not change over time. At 24-36 hours of age, triiodothyronine (T3) was significantly lower in both premature and term hospitalized foals compared to normal foals; premature foals were not different from term hospitalized foals. Thyroxine (T4) was not different between normal and term hospitalized foals, but was significantly lower than in premature foals of both of these groups. TSH was not different among the 3 groups. TRH stimulation tests identified significant differences in T4 among all 3 groups of foals, whereas T3 was similar in premature and term hospitalized foals and different from normal foals. TSH response to TRH was significantly higher in premature foals compared to normal foals. CONCLUSIONS AND CLINICAL IMPORTANCE: The hypothalamic-pituitary-thyroid axis is different in foals compared to adult horses. Sick foals exhibit nonthyroidal illness syndrome. Premature foals are more markedly hypothyroxinemic than can be accounted for by their severity of illness alone.


Assuntos
Animais Recém-Nascidos/fisiologia , Doenças dos Cavalos/fisiopatologia , Nascimento Prematuro/veterinária , Hormônios Tireóideos/sangue , Animais , Animais Recém-Nascidos/sangue , Doenças dos Cavalos/sangue , Cavalos , Doenças da Glândula Tireoide/sangue , Doenças da Glândula Tireoide/fisiopatologia , Doenças da Glândula Tireoide/veterinária , Glândula Tireoide/fisiologia , Hormônios Tireóideos/fisiologia , Tireotropina/sangue , Tireotropina/fisiologia , Tiroxina/sangue , Tiroxina/fisiologia , Tri-Iodotironina/sangue , Tri-Iodotironina/fisiologia
16.
J Endocrinol ; 221(3): R87-R103, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24648121

RESUMO

The thyroid hormones, thyroxine (T4) and triiodothyronine (T3), are essential for normal growth and development of the fetus. Their bioavailability in utero depends on development of the fetal hypothalamic-pituitary-thyroid gland axis and the abundance of thyroid hormone transporters and deiodinases that influence tissue levels of bioactive hormone. Fetal T4 and T3 concentrations are also affected by gestational age, nutritional and endocrine conditions in utero, and placental permeability to maternal thyroid hormones, which varies among species with placental morphology. Thyroid hormones are required for the general accretion of fetal mass and to trigger discrete developmental events in the fetal brain and somatic tissues from early in gestation. They also promote terminal differentiation of fetal tissues closer to term and are important in mediating the prepartum maturational effects of the glucocorticoids that ensure neonatal viability. Thyroid hormones act directly through anabolic effects on fetal metabolism and the stimulation of fetal oxygen consumption. They also act indirectly by controlling the bioavailability and effectiveness of other hormones and growth factors that influence fetal development such as the catecholamines and insulin-like growth factors (IGFs). By regulating tissue accretion and differentiation near term, fetal thyroid hormones ensure activation of physiological processes essential for survival at birth such as pulmonary gas exchange, thermogenesis, hepatic glucogenesis, and cardiac adaptations. This review examines the developmental control of fetal T4 and T3 bioavailability and discusses the role of these hormones in fetal growth and development with particular emphasis on maturation of somatic tissues critical for survival immediately at birth.


Assuntos
Desenvolvimento Fetal/fisiologia , Troca Materno-Fetal/fisiologia , Tiroxina/fisiologia , Tri-Iodotironina/fisiologia , Feminino , Humanos , Sistema Hipotálamo-Hipofisário/embriologia , Sistema Hipotálamo-Hipofisário/fisiologia , Modelos Biológicos , Sistema Hipófise-Suprarrenal/embriologia , Sistema Hipófise-Suprarrenal/fisiologia , Gravidez , Tiroxina/metabolismo , Tri-Iodotironina/metabolismo
17.
Mol Endocrinol ; 28(5): 745-57, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24673558

RESUMO

T4 (3,5,3',5'-tetraiodo-l-thyronine) is classically viewed as a prohormone that must be converted to the T3 (3,5,3'-triiodo-l-thyronine) form for biological activity. We first determined that the ability of reporter genes to respond to T4 and to T3 differed for the different thyroid hormone receptor (TR) isoforms, with TRα1 generally more responsive to T4 than was TRß1. The response to T4 vs T3 also differed dramatically in different cell types in a manner that could not be attributed to differences in deiodinase activity or in hormone affinity, leading us to examine the role of TR coregulators in this phenomenon. Unexpectedly, several coactivators, such as steroid receptor coactivator-1 (SRC1) and thyroid hormone receptor-associated protein 220 (TRAP220), were recruited to TRα1 nearly equally by T4 as by T3 in vitro, indicating that TRα1 possesses an innate potential to respond efficiently to T4 as an agonist. In contrast, release of corepressors, such as the nuclear receptor coreceptor NCoRω, from TRα1 by T4 was relatively inefficient, requiring considerably higher concentrations of this ligand than did coactivator recruitment. Our results suggest that cells, by altering the repertoire and abundance of corepressors and coactivators expressed, may regulate their ability to respond to T4, raising the possibility that T4 may function directly as a hormone in specific cellular or physiological contexts.


Assuntos
Receptores alfa dos Hormônios Tireóideos/metabolismo , Receptores beta dos Hormônios Tireóideos/metabolismo , Tiroxina/fisiologia , Células 3T3-L1 , Animais , Células CHO , Cricetinae , Cricetulus , Células HEK293 , Células HeLa , Células Hep G2 , Humanos , Camundongos , Isoformas de Proteínas/agonistas , Isoformas de Proteínas/metabolismo , Transdução de Sinais , Receptores alfa dos Hormônios Tireóideos/agonistas , Receptores beta dos Hormônios Tireóideos/agonistas , Ativação Transcricional , Tri-Iodotironina/fisiologia
18.
J Vet Intern Med ; 28(2): 609-17, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24417524

RESUMO

BACKGROUND: This study was performed to determine whether sick horses have thyroid hormone (TH) alterations similar to those observed in nonthyroidal illness syndrome in other species. HYPOTHESIS: Horses suffering from systemic diseases have decreased THs and inappropriately low thyroid-stimulating hormone (TSH). ANIMALS: Seventy-one clinically normal horses; 380 hospitalized horses. METHODS: Total thyroxine (TT4), free thyroxine by equilibrium dialysis (fT4D), total triiodothyronine (TT3), free triiodothyronine (fT3), and TSH were measured in normal and hospitalized horses. Disease severity was categorized as mild, moderate, or severe by both subjective and objective criteria. RESULTS: Negative correlations existed between all THs, except TSH, and objective illness severity scores. These scores also increased with each subjective disease severity category. TT3 and fT3 were decreased with mild disease. TT3 progressively decreased more with moderate and severe disease. TT4 and fT4D remained normal with mild disease, but decreased progressively with disease severity. TSH increased with mild disease, but remained normal with moderate or severe disease. Horses that died or were euthanized had lower concentrations of all THs, except TSH, when compared with those that lived. In horses that received >3 doses of NSAIDs, corticosteroids, or heparin compared to 0-3 doses, TT3 and TT4 were decreased, whereas fT4D and TSH remained normal. There were minimal TH changes in horses that were not eating. CONCLUSIONS AND CLINICAL IMPORTANCE: Thyroid hormones decrease in horses with systemic disease. TT3 decreases first, followed by TT4 and fT4D. TSH fails to increase proportionally to the changes in THs, indicating hypothalamic-pituitary axis dysregulation. NSAIDs, corticosteroids, heparin, and fasting have less effect on THs compared with disease severity.


Assuntos
Doenças dos Cavalos/fisiopatologia , Hormônios Tireóideos/sangue , Animais , Estudos de Casos e Controles , Feminino , Doenças dos Cavalos/sangue , Cavalos , Masculino , Índice de Gravidade de Doença , Síndrome , Glândula Tireoide/fisiopatologia , Hormônios Tireóideos/fisiologia , Tireotropina/sangue , Tireotropina/fisiologia , Tiroxina/sangue , Tiroxina/fisiologia , Tri-Iodotironina/sangue , Tri-Iodotironina/fisiologia
19.
J Clin Invest ; 124(1): 321-7, 2014 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-24316972

RESUMO

Central congenital hypothyroidism (CCH) is more prevalent in children born to women with hyperthyroidism during pregnancy, suggesting a role for thyroid hormone (TH) in the development of central thyroid regulation. Using the zebrafish embryo as a model for thyroid axis development, we have characterized the ontogeny of negative feedback regulation of thyrotrope function and examined the effect of excess TH on thyrotrope development. We found that thyroid-stimulating hormone ß subunit (tshb) and type 2 deiodinase (dio2) are coexpressed in zebrafish thyrotropes by 48 hours after fertilization and that TH-driven negative feedback regulation of tshb transcription appears in the thyroid axis by 96 hours after fertilization. Negative feedback regulation correlated with increased systemic TH levels from the developing thyroid follicles. We used a transgenic zebrafish that expresses GFP under the control of the tshb promoter to follow thyrotrope fates in vivo. Time-lapse imaging revealed that early exposure to elevated TH leads to thyrotrope cell death. Thyrotrope numbers slowly recovered following the removal of excess TH. These data demonstrate that transient TH exposure profoundly impacts the thyrotrope population during a critical period of pituitary development and may have long-term implications for the functional reserve of thyroid-stimulating hormone (TSH) production and the TSH set point later in life.


Assuntos
Apoptose , Hormônios Tireóideos/fisiologia , Tireotrofos/fisiologia , Tiroxina/fisiologia , Animais , Animais Geneticamente Modificados , Diferenciação Celular , Hipotireoidismo Congênito/metabolismo , Hipotireoidismo Congênito/patologia , Embrião não Mamífero/patologia , Retroalimentação Fisiológica , Feminino , Humanos , Iodeto Peroxidase/metabolismo , Gravidez , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/patologia , Tireotropina Subunidade beta/metabolismo , Peixe-Zebra , Proteínas de Peixe-Zebra/metabolismo
20.
J Neurosci ; 33(44): 17232-46, 2013 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-24174657

RESUMO

Intraventricular hemorrhage (IVH) remains a major cause of white matter injury in preterm infants with no viable therapeutic strategy to restore myelination. Maturation of oligodendrocytes and myelination is influenced by thyroid hormone (TH) signaling, which is mediated by TH receptor α (TRα) and TRß. In the brain, cellular levels of TH are regulated by deiodinases, with deiodinase-2 mediating TH activation and deiodinase-3 TH inactivation. Therefore, we hypothesized that IVH would decrease TH signaling via changes in the expression of deiodinases and/or TRs, and normalization of TH signaling would enhance maturation of oligodendrocytes and myelination in preterm infants with IVH. These hypotheses were tested using both autopsy materials from human preterm infants and a rabbit model of IVH. We found that deiodinase-2 levels were reduced, whereas deiodinase-3 levels were increased in brain samples of both humans and rabbits with IVH compared with controls without IVH. TRα expression was also increased in human infants with IVH. Importantly, treatment with TH accelerated the proliferation and maturation of oligodendrocytes, increased transcription of Olig2 and Sox10 genes, augmented myelination, and restored neurological function in pups with IVH. Consistent with these findings, the density of myelinating oligodendrocytes was almost doubled in TH-treated human preterm infants compared with controls. Thus, in infants with IVH the combined elevation in deiodinase-3 and reduction in deiodinase-2 decreases TH signaling that can be worsened by an increase in unliganded TRα. Given that TH promotes neurological recovery in IVH, TH treatment might improve the neurodevelopmental outcome of preterm infants with IVH.


Assuntos
Hemorragia Cerebral/tratamento farmacológico , Hemorragia Cerebral/fisiopatologia , Ventrículos Cerebrais/fisiopatologia , Bainha de Mielina/fisiologia , Recuperação de Função Fisiológica/fisiologia , Tiroxina/fisiologia , Animais , Animais Recém-Nascidos , Ventrículos Cerebrais/fisiologia , Modelos Animais de Doenças , Método Duplo-Cego , Feminino , Humanos , Recém-Nascido , Recém-Nascido Prematuro , Masculino , Bainha de Mielina/patologia , Coelhos , Tiroxina/uso terapêutico , Resultado do Tratamento
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