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1.
Eur J Endocrinol ; 184(1): 1-8, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33112257

RESUMO

Objective: Somatostatin receptor ligands (SRL) are useful to control central hyperthyroidism in patients with thyrotropin-secreting pituitary adenoma (TSH pituitary adenoma). The aim of this study was to describe the frequency of thyrotropin deficiency (TSH deficiency) in patients with TSH pituitary adenoma treated by SRL. Design: Retrospective study. Methods: Patients with central hyperthyroidism due to TSH pituitary adenoma treated by short or long-acting SRL were retrospectively included. TSH deficiency was defined by a low FT4 associated with non-elevated TSH concentrations during SRL therapy. We analysed the frequency of TSH deficiency and the characteristics of patients with or without TSH deficiency. Results: Forty-six patients were included. SRL were used as the first-line therapy in 21 of 46 patients (46%). Central hyperthyroidism was controlled in 36 of 46 patients (78%). TSH deficiency appeared in 7 of 46 patients (15%) after a median time of 4 weeks (4-7) and for a median duration of 3 months (2.5-3). The TSH deficiency occurred after one to three injections of long-acting SRL used as first-line therapy in 6/7 cases. There were no differences in terms of clinical and hormonal features, size of adenomas or doses of SRL between patients with or without TSH deficiency. Conclusions: SRL can induce TSH deficiency in patients with central hyperthyroidism due to TSH pituitary adenoma. Thyrotropic function should be assessed before the first three injections of SRL in order to track TSH deficiency and reduce the frequency of injections when control of thyrotoxicosis rather than tumour reduction is the aim of the treatment.


Assuntos
Adenoma/complicações , Hipertireoidismo/tratamento farmacológico , Hipotireoidismo/induzido quimicamente , Neoplasias Hipofisárias/complicações , Receptores de Somatostatina/uso terapêutico , Adenoma/metabolismo , Adulto , Feminino , Humanos , Hipertireoidismo/etiologia , Ligantes , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/metabolismo , Estudos Retrospectivos , Tireotropina/metabolismo
2.
Environ Health Prev Med ; 25(1): 69, 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33153430

RESUMO

BACKGROUND: The absence of thyroid cysts may indicate latent thyroid damage, as demonstrated in our previous study. However, the association between the absence of thyroid cysts and latent functional damage of the thyroid is unknown. At low thyroid hormone productivity, which may be associated with latent functional damage of the thyroid, the association between thyroid-stimulating hormone (TSH) and hypertension might be enhanced. Therefore, we evaluated the association between TSH level and hypertension stratified by thyroid cyst status. METHODS: We conducted a cross-sectional study of 1724 euthyroid Japanese individuals aged 40-74 years who participated in an annual health checkup in 2014. RESULTS: In the study population, 564 and 686 participants had thyroid cysts and hypertension, respectively. A significant positive association was observed between TSH and hypertension in subjects without a thyroid cyst but not in subjects with thyroid cysts. There was a significant positive association between hypertension and TSH in subjects without a thyroid cyst (odds ratio [OR] 1.27; 95% confidence intervals [CI] 1.01, 1.61) but not in subjects with thyroid cysts (OR 0.79; CI 0.57, 1.09) in the model fully adjusted for known confounding factors. The correlation between the TSH and free triiodothyronine (fee T3) levels (simple correlation coefficient [r] = - 0.13, p < 0.01) was stronger in the subjects without thyroid cysts than in those with thyroid cysts (r = - 0.03, p = 0.525). CONCLUSIONS: TSH is positively associated with hypertension only in individuals without thyroid cysts. The correlation between the TSH and free T3 levels was stronger in the subjects without thyroid cysts than in those with thyroid cysts. Therefore, the absence of thyroid cysts could be related to the association between TSH level and hypertension, possibly by indicating that the subjects without thyroid cysts had limited thyroid hormone reserves. Therefore, the absence of thyroid cysts could indicate the latent functional damage of the thyroid.


Assuntos
Cistos/etiologia , Hipertensão/metabolismo , Doenças da Glândula Tireoide/etiologia , Glândula Tireoide/patologia , Tireotropina/metabolismo , Idoso , Estudos Transversais , Feminino , Humanos , Hipertensão/etiologia , Japão , Masculino , Pessoa de Meia-Idade
3.
Clin Nucl Med ; 45(9): 719-721, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32657858

RESUMO

We report a case of a 66-year-old woman with small cell lung cancer (stage IIB, T2N1M0), who received immunotherapy with nivolumab monthly for 2 months and then presented with thyrotoxic symptoms associated with suppressed thyroid-stimulating hormone levels and elevated free thyroid hormone levels, although previous thyrotropin performed 1 month ago was normal. Thyroid uptake and scan demonstrated diffusely decreased uptake in both thyroid lobes. The 4-hour percentage uptake was 0.7%, and the 24-hour percentage uptake was 0.3%. This was followed by development of hypothyroidism within few weeks. Findings suggested drug-induced thyroiditis secondary to nivolumab therapy.


Assuntos
Imunoterapia/efeitos adversos , Medicina Nuclear , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/fisiopatologia , Idoso , Feminino , Humanos , Neoplasias Pulmonares/terapia , Nivolumabe/efeitos adversos , Carcinoma de Pequenas Células do Pulmão/terapia , Glândula Tireoide/diagnóstico por imagem , Glândula Tireoide/metabolismo , Tireotropina/metabolismo , Tiroxina/metabolismo
5.
Orv Hetil ; 161(12): 474-478, 2020 Mar.
Artigo em Húngaro | MEDLINE | ID: mdl-32172585

RESUMO

Thyrotropin-secreting pituitary tumors are rare causes of hyperthyroidism and account for less than 1% of all pituitary adenomas. The number of reported cases increased over the last few years as a consequence of the routine use of ultrasensitive immunometric assays for measuring thyrotropin levels. In the clinical practice, thyrotropin secreting adenomas must be considered in case of inappropriately normal to elevated thyrotropin in the presence of elevated free serum thyroid hormone levels. The authors present the case history of a middle aged female patient, who suffered from hyperthyreodism caused by a thyrotropin-secreting pituitary macroadenoma. After transient thyreostatic treatment, radical neurosurgical removal of the tumor was performed. The pituitary surgery was effective in restoring the patient's euthyreodism. The postoperative pituitary function remained intact. During follow-up, the recurrence of the disease was not detected. In our case report, the difficulties in the differential diagnoses are also discussed. Orv Hetil. 2020; 161(12): 474-478.


Assuntos
Adenoma/metabolismo , Adenoma/cirurgia , Hipertireoidismo/etiologia , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/cirurgia , Tireotropina/metabolismo , Adenoma/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Neoplasias Hipofisárias/patologia , Testes de Função Tireóidea , Tireotropina/sangue , Resultado do Tratamento
6.
J Immunol ; 204(7): 1724-1735, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32086386

RESUMO

IL-23 and IL-12, two structurally related heterodimeric cytokines sharing a common subunit, divergently promote Th cell development and expansion. Both cytokines have been implicated in the pathogenesis of thyroid-associated ophthalmopathy (TAO), an autoimmune component of Graves disease. In TAO, CD34+ fibrocytes, putatively derived from bone marrow, can be identified in the orbit. There they masquerade as CD34+ orbital fibroblasts (OF) (CD34+ OF) and cohabitate with CD34- OF in a mixed fibroblast population (GD-OF). Slit2, a neural axon repellent, is expressed and released by CD34- OF and dampens the inflammatory phenotype of fibrocytes and CD34+ OF. In this study we report that thyrotropin (TSH) and the pathogenic, GD-specific monoclonal autoantibody, M22, robustly induce IL-23 in human fibrocytes; however, IL-12 expression is essentially undetectable in these cells under basal conditions or following TSH-stimulation. In contrast, IL-12 is considerably more inducible in GD-OF, cells failing to express IL-23. This divergent expression and induction of cytokines appears to result from cell type-specific regulation of both gene transcription and mRNA stabilities. It appears that the JNK pathway activity divergently attenuates IL-23p19 expression while enhancing that of IL-12p35. The shift from IL-23p19 expression in fibrocytes to that of IL-12p35 in their derivative CD34+ OF results from the actions of Slit2. Thus, Slit2 might represent a molecular determinant of balance between IL-23 and IL-12 expression, potentially governing immune responses in TAO.


Assuntos
Fibroblastos/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Proteínas do Tecido Nervoso/imunologia , Tireotropina/metabolismo , Antígenos CD34/metabolismo , Células Cultivadas , Citocinas/metabolismo , Doença de Graves/metabolismo , Oftalmopatia de Graves/metabolismo , Humanos , Órbita/metabolismo , Estabilidade de RNA/fisiologia , Receptores da Tireotropina/metabolismo , Transdução de Sinais/fisiologia
7.
Acta Odontol Scand ; 78(5): 337-344, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32031461

RESUMO

Objective: An association between hypothyroidism (HT) and oral lichen planus (OLP) has been reported. However, the mechanisms that could explain this association remain unresolved. This study aimed to evaluate the expression of thyroid-stimulating hormone (TSH) and thyroid-stimulating hormone receptor (TSHR) in healthy oral mucosa and in OLP lesions of individuals with and without HT.Material and methods: Immunohistochemical expression of TSH and TSHR was studied in oral mucosal biopsies obtained from 14 OLP patients with HT, 14 OLP patients without HT and 10 healthy controls without oral mucosal lesions. Gene expression of TSHR was investigated by using three different PCR techniques in oral mucosal samples from 7 OLP patients with HT, 3 OLP patients without HT, 9 healthy controls and in cultured human oral epithelial cells. Gene expression of TSH was examined by employing 2 PCR techniques in oral mucosal samples from 2 OLP patients with HT, 2 OLP patients without HT and 4 healthy controls.Results: TSH and TSHR stainings were negative in the studied oral mucosal specimens. Gene quantification assays demonstrated negative gene expression of TSH and TSHR in clinical and in vitro samples.Conclusions: These results suggest that TSH and TSHR may not be commonly involved in the pathogenetic mechanism that could explain the association between OLP and hypothyroidism.


Assuntos
Hipotireoidismo/sangue , Líquen Plano Bucal/metabolismo , Mucosa Bucal/metabolismo , Receptores da Tireotropina/sangue , Receptores da Tireotropina/metabolismo , Tireotropina/sangue , Tireotropina/metabolismo , Estudos de Casos e Controles , Humanos , Líquen Plano Bucal/genética , Líquen Plano Bucal/patologia , Mucosa Bucal/patologia , Reação em Cadeia da Polimerase , Receptores da Tireotropina/genética , Tireotropina/genética
8.
Endocrinology ; 161(2)2020 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-31913463

RESUMO

Dietary vitamin A is metabolized into bioactive retinoic acid (RA) in vivo and regulates the development of many embryonic tissues. RA signaling is active in the oral ectoderm-derived tissues of the neuroendocrine system, but its role there has not yet been fully explored. We show here that RA signaling is active during pituitary organogenesis and dependent on the pituitary transcription factor Prop1. Prop1-mutant mice show reduced expression of the aldehyde dehydrogenase gene Aldh1a2, which metabolizes the vitamin A-intermediate retinaldehyde into RA. To elucidate the specific function of RA signaling during neuroendocrine development, we studied a conditional deletion of Aldh1a2 and a dominant-negative mouse model of inhibited RA signaling during pituitary organogenesis. These models partially phenocopy Prop1-mutant mice by exhibiting embryonic pituitary dysmorphology and reduced hormone expression, especially thyrotropin. These findings establish the role of RA in embryonic pituitary stem cell progression to differentiated hormone cells and raise the question of gene-by-environment interactions as contributors to pituitary development and disease.


Assuntos
Aldeído Desidrogenase 1/metabolismo , Proteínas de Homeodomínio/metabolismo , Hipófise/embriologia , Retinal Desidrogenase/metabolismo , Tretinoína/metabolismo , Aldeído Desidrogenase 1/genética , Animais , Camundongos Endogâmicos C57BL , Organogênese , Hipófise/metabolismo , Retinal Desidrogenase/genética , Transdução de Sinais , Células-Tronco/metabolismo , Tireotropina/metabolismo
9.
PLoS One ; 15(1): e0227646, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31940421

RESUMO

The serum concentration of thyrotropin (thyroid stimulating hormone, TSH) is drastically reduced by small increase in the levels of thyroid hormones (T3 and its prohormone, T4); however, the mechanism underlying this relationship is unknown. TSH consists of the chorionic gonadotropin α (CGA) and the ß chain (TSHß). The expression of both peptides is induced by the transcription factor GATA2, a determinant of the thyrotroph and gonadotroph differentiation in the pituitary. We previously reported that the liganded T3 receptor (TR) inhibits transactivation activity of GATA2 via a tethering mechanism and proposed that this mechanism, but not binding of TR with a negative T3-responsive element, is the basis for the T3-dependent inhibition of the TSHß and CGA genes. Multiple GATA-responsive elements (GATA-REs) also exist within the GATA2 gene itself and mediate the positive feedback autoregulation of this gene. To elucidate the effect of T3 on this non-linear regulation, we fused the GATA-REs at -3.9 kb or +9.5 kb of the GATA2 gene with the chloramphenicol acetyltransferase reporter gene harbored in its 1S-promoter. These constructs were co-transfected with the expression plasmids for GATA2 and the pituitary specific TR, TRß2, into kidney-derived CV1 cells. We found that liganded TRß2 represses the GATA2-induced transactivation of these reporter genes. Multi-dimensional input function theory revealed that liganded TRß2 functions as a classical transcriptional repressor. Then, we investigated the effect of T3 on the endogenous expression of GATA2 protein and mRNA in the gonadotroph-derived LßT2 cells. In this cell line, T3 reduced GATA2 protein independently of the ubiquitin proteasome system. GATA2 mRNA was drastically suppressed by T3, the concentration of which corresponds to moderate hypothyroidism and euthyroidism. These results suggest that liganded TRß2 inhibits the positive feedback autoregulation of the GATA2 gene; moreover this mechanism plays an important role in the potent reduction of TSH production by T3.


Assuntos
Fator de Transcrição GATA2/metabolismo , Receptores dos Hormônios Tireóideos/metabolismo , Tireotropina/metabolismo , Animais , Linhagem Celular , Fator de Transcrição GATA2/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Genes Reporter/efeitos dos fármacos , Genes Reporter/genética , Subunidade alfa de Hormônios Glicoproteicos , Homeostase/efeitos dos fármacos , Ligantes , Camundongos , Regiões Promotoras Genéticas/efeitos dos fármacos , Regiões Promotoras Genéticas/genética , Ratos , Receptores dos Hormônios Tireóideos/genética , Hormônios Tireóideos/metabolismo , Tireotrofos/metabolismo , Tireotropina/análise , Tireotropina/sangue , Tireotropina Subunidade beta/genética , Tireotropina Subunidade beta/metabolismo , Fatores de Transcrição/metabolismo , Ativação Transcricional/efeitos dos fármacos , Ativação Transcricional/genética , Tri-Iodotironina/metabolismo
10.
Oxid Med Cell Longev ; 2020: 1249630, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31998431

RESUMO

Background & Aims: Oxidative stress-related liver diseases were shown to be associated with elevated serum thyroid stimulating hormone (TSH) levels. Mitochondria are the main source of cellular reactive oxygen species. However, the relationship between TSH and hepatic mitochondrial stress/dysfunction and the underlying mechanisms are largely unknown. Here, we focused on exploring the effects and mechanism of TSH on hepatic mitochondrial stress. Methods: As the function of TSH is mediated through the TSH receptor (TSHR), Tshr -/- mice and liver-specific Tshr -/- mice and liver-specific Tshr -/- mice and liver-specific. Results: A relatively lower degree of mitochondrial stress was observed in the livers of Tshr -/- mice and liver-specific in vitro. Microarray and RT-PCR analyses showed that Tshr -/- mice and liver-specific. Conclusions: TSH stimulates hepatic CypD acetylation through the lncRNA-AK044604/SIRT1/SIRT3 signaling pathway, indicating an essential role for TSH in mitochondrial stress in the liver.


Assuntos
Ciclofilina D/metabolismo , Fígado/enzimologia , Mitocôndrias Hepáticas/enzimologia , Estresse Oxidativo , Tireotropina/metabolismo , Acetilação , Animais , Ciclofilina D/genética , Camundongos , Camundongos Knockout , Mitocôndrias Hepáticas/genética , Receptores da Tireotropina/genética , Receptores da Tireotropina/metabolismo , Tireotropina/genética
11.
Chemosphere ; 241: 125118, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31683416

RESUMO

Deltamethrin (DM) has become one of the most widely used insecticides in the world due to its low toxicity, high efficiency and low persistence in soil. However, it is still unknown whether DM exposure has any effects on the Hypothalamic-Pituitary-Thyroid (HPT) axis in adolescent mice. In this study, the open field test and circadian activity test showed that DM exposure increased activity. There was no significant difference between the groups in the light/dark box test and nest building test. Forced swimming test showed that after 6 and 12 mg kg-1 DM exposure 28 days, the immobility time was increased and the swimming time was reduced. After 6 mg kg-1 DM treatment, the thyroid stimulating hormone (TSH) content increased, and thyrotropin releasing hormone (TRH), triiodothyronine (T3) and thyroxine (T4) decreased. After exposure to 6 and 12 mg kg-1 DM, mRNA levels of HPT axis-related genes were destroyed. The histological examination showed that, the DM groups mice thyroid tissues appeared expanded thyroid follicles, scanty colloid and hyperplastic thyroid cells. Western blot results showed that the expression level of tyrosine hydroxylase (TH) protein decreased and the content of dopamine transporter (DAT) protein increased in DM treated mice striatum. Collectively, our results indicated that DM exposure could induce thyroid dysfunction and behavioral disorders in adolescent mice.


Assuntos
Transtornos Mentais/induzido quimicamente , Nitrilos/farmacologia , Piretrinas/farmacologia , Glândula Tireoide/fisiopatologia , Hormônios Tireóideos/metabolismo , Envelhecimento , Animais , Comportamento Animal/efeitos dos fármacos , Inseticidas/farmacologia , Masculino , Camundongos , Glândula Tireoide/metabolismo , Tireotropina/metabolismo , Hormônio Liberador de Tireotropina/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina/metabolismo
12.
Toxicol Appl Pharmacol ; 389: 114873, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31881178

RESUMO

Fipronil is a phenylpyrazole insecticide used for the control of a variety of pest for domestic, veterinary and agricultural uses. Fipronil exposure is associated to thyroid disruption in the rat. It increases thyroid hormone (TH) hepatic clearance. The effect on thyroxine (T4) clearance is about four fold higher than the effect on T4 plasma concentrations suggesting that the thyroid gland might develop compensatory mechanisms. The aim of this study was to document the potential effects of fipronil treatment on the thyroid transcriptome together with its effects on TSH and TH blood levels under well characterized internal exposure to fipronil and its main metabolite fipronil sulfone. Fipronil (3 mg/kg/d by gavage for 14 days) clearance increased while its half-life decreased (about 10 fold) throughout treatment. Fipronil treatment in adult female rats significantly decreased total T4 and free triiodothyronine (T3) concentrations. Key genes related to thyroid hormone synthesis and/or cellular dynamic were modulated by fipronil exposure. RT-PCR confirmed that thyroglobulin gene expression was upregulated. A trend toward higher Na/I symporter expression was also noted, while sulfotransferase 1a1 gene expression was down-regulated. The expression of genes potentially involved in thyroid cell dynamic were upregulated (e.g. prostaglandin synthase 1, amphiregulin and Rhoa). Our results indicate that both pathways of TH synthesis and thyroid cell dynamics are transcriptional targets of fipronil and/or its main sulfone metabolite. The underlying mechanisms remain to be elucidated.


Assuntos
Pirazóis/farmacologia , Glândula Tireoide/efeitos dos fármacos , Transcriptoma/efeitos dos fármacos , Animais , Feminino , Inseticidas/farmacologia , Ratos , Ratos Wistar , Testes de Função Tireóidea/métodos , Hormônios Tireóideos/metabolismo , Tireotropina/metabolismo , Tiroxina/metabolismo , Tri-Iodotironina/metabolismo
13.
BMC Pregnancy Childbirth ; 19(1): 476, 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31805890

RESUMO

BACKGROUND: Hypothyroidism in pregnancy is an arena of ongoing research, with international conflicts regarding screening, management, and outcomes. Various studies have described the outcomes depending on geographical and international diagnostic criteria. No study has been conducted in this regard from the region of Pakistan. Therefore, we aim to report the clinical features and maternal outcomes of hypothyroid pregnancies and compare the maternal outcomes between uncontrolled and controlled TSH levels in the preconception as well as the gestational period. METHODS: We conducted a cross-sectional retrospective study on 718 cases in the Aga Khan University Hospital after ethical approval. We collected information on pregnant females who have diagnosed hypothyroidism before conception or during their antenatal period. We noted the maternal characteristics and maternal comorbidities. Laboratory data were recorded for thyroid stimulating hormone levels before conception and during gestation. We recorded maternal outcomes as pregnancy loss (including miscarriage, stillbirth/intrauterine death, medical termination of pregnancy and ectopic pregnancy), gestational hypertension, pre-eclampsia, postpartum hemorrhage, placental abruption, and modalities of delivery. Data analysis was performed on Statistical Package for the Social Sciences version 20.0. RESULTS: Among 708 hypothyroid women 638 had live births. Postpartum hemorrhage was the most frequent maternal outcome (38.8%). The emergency cesarean section occurred in 23.4% of cases. We determined TSH levels in 53.2, 56.7, 61.7 and 66.6% of cases in preconception, 1st, 2nd, and 3rd trimester periods. A significant association existed between cesarean section and preconception thyrotropin levels > 2.5 mIU/L, whereas postpartum hemorrhage was significantly associated with thyrotropin levels > 2.5 mIU/L in the preconception and third trimester. CONCLUSION: Successful live births in our patients were complicated by maternal postpartum hemorrhage and a frequent number of emergency cesarean section.


Assuntos
Cesárea/estatística & dados numéricos , Hipotireoidismo/complicações , Hemorragia Pós-Parto/epidemiologia , Complicações na Gravidez/epidemiologia , Resultado da Gravidez , Aborto Espontâneo/epidemiologia , Adolescente , Adulto , Estudos de Casos e Controles , Estudos Transversais , Feminino , Humanos , Hipertensão Induzida pela Gravidez/epidemiologia , Pessoa de Meia-Idade , Paquistão , Pré-Eclâmpsia/epidemiologia , Gravidez , Estudos Retrospectivos , Tireotropina/metabolismo , Fatores de Tempo , Adulto Jovem
14.
Reprod Biol Endocrinol ; 17(1): 90, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699106

RESUMO

OBJECTIVE: The objective ofthis study was to assess the association between thyroid hormone (TH) levels in follicular fluid (FF) and serum and to determine whether THs impact assisted reproductive technology (ART) outcomes. METHODS: This study enrolled 299 women undergoing ART. Blood samples were drawn on the day of human chorionic gonadotrophin (HCG) administrationand analysed for thyroid-stimulating hormone (TSH), thyroxine(T4), triiodothyronine(T3),free T4 (fT4),free T3(fT3), thyroid peroxidase antibody (TPOAb) and thyroglobulin antibody (TGAb) levels. FF was obtained on the oocyte pick up (OPU) day and analysed forTSH, T4, T3, fT4, fT3, TPOAb, TgAb and estradiol levels. RESULTS: (1) There were significant positive correlations between serum and FF TH and thyroid autoantibody levels. Statistically significant differences were discovered in serum and FF levels of TSH (p ≤ 0.001), T4 (p ≤ 0.001), T3 (p ≤ 0.001), TPOAbs (p ≤ 0.001) and TGAbs (p = 0.021). (2) Serum T4 levels [121.9(104.8,140.8) vs 114.1(98.6,130.6) nmol/l, p = 0.026], serum fT4 levels[(19.0(17.7,21.8) vs 18.6(17.0,20.1) pmol/l, p = 0.026], serum T4/T3 ratios [62.5 (55.7, 66.2) vs 59.4 (53.4, 64.9), p = 0.029], FF fT4 levels [19.0(17.5,21.3) vs 18.1(16.8,19.9) pmol/l, p = 0.009] and FF T4/T3 ratios [52.6 (46.4, 57.3) vs 50.0 (43.7, 53.1), p = 0.004] were significantly higher in the successful pregnancy group than the implantation failure group. (3) Spearman's rank correlation analysis revealed positive associations of both the FF T4/T3 ratio and serum TSH levels with the numbers of retrieved oocytes (total or MII) and embryos (fertilized, cleavage, and good quality). CONCLUSIONS: TH levels in FF are strongly correlated with those in serum on the HCG day, and THs on the HCG day may affect ART outcomes.


Assuntos
Líquido Folicular/metabolismo , Técnicas de Reprodução Assistida , Hormônios Tireóideos/sangue , Hormônios Tireóideos/metabolismo , Adulto , Autoanticorpos/sangue , Autoanticorpos/metabolismo , Implantação do Embrião , Feminino , Humanos , Avaliação de Resultados em Cuidados de Saúde , Gravidez , Taxa de Gravidez , Tireotropina/sangue , Tireotropina/metabolismo , Tiroxina/sangue , Tiroxina/metabolismo , Tri-Iodotironina/sangue , Tri-Iodotironina/metabolismo
15.
Horm Metab Res ; 51(11): 691-702, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31683338

RESUMO

The purpose of this meta-analysis was to determine whether patients with subclinical hypothyroidism (SCH) have impaired endothelial function, which is assessed by carotid intima-media thickness (C-IMT) and flow-mediated dilatation (FMD) of brachial artery. PubMed, Embase and Cochrane Library databases and the key studies references were searched in our study, prior to July 2017 for all language articles about FMD or C-IMT in SCH and euthyroid subjects. Two authors screened documents and extracted data by pre-established standard independently. The pooled estimate for continuous data was calculated using random-effects models. Statistical heterogeneity was evaluated using I2 statistics. Subgroup analyses were conducted to assess the robustness of the meta-analysis. Publication bias was examined with funnel plot analysis and Egger's test. In this meta-analysis, 10 studies with 760 subjects are related to FMD with SCH and 23 studies with 1521 subjects are related to C-IMT with SCH. The pooled estimate of the weighted mean difference (WMD) has revealed that SCH correlated with increased C-IMT [WMD 0.069 mm; 95% CI (0.042, 0.095); p<0.001] and decreased FMD [WMD -1.848%; 95% CI (-2.298, -1.399); p<0.001] with high heterogeneity.: Compared with EU controls, SCH was also associated with an increased diastolic blood pressure (DBP), systolic blood pressure (SBP), triglyceride (TG), total cholesterol (TC) levels, and low density lipoprotein cholesterol (LDL-C). This meta-analysis demonstrates that SCH is associated with endothelial dysfunction, which may relate with increased thyroid-stimulating hormone (TSH). Hypertension and dyslipidemia may play a crucial part in the development of endothelial dysfunction.


Assuntos
Dislipidemias/complicações , Endotélio Vascular/patologia , Hipertensão/complicações , Hipotireoidismo/etiologia , Endotélio Vascular/metabolismo , Humanos , Hipotireoidismo/patologia , Tireotropina/metabolismo
16.
BMJ ; 366: l4892, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31481394

RESUMO

OBJECTIVE: To explore whether thyroid stimulating hormone (TSH) concentration in patients with a diagnosis of hypothyroidism is associated with increased all cause mortality and a higher risk of cardiovascular disease and fractures. DESIGN: Retrospective cohort study. SETTING: The Health Improvement Network (THIN), a database of electronic patient records from UK primary care. PARTICIPANTS: Adult patients with incident hypothyroidism from 1 January 1995 to 31 December 2017. EXPOSURE: TSH concentration in patients with hypothyroidism. MAIN OUTCOME MEASURES: Ischaemic heart disease, heart failure, stroke/transient ischaemic attack, atrial fibrillation, any fractures, fragility fractures, and mortality. Longitudinal TSH measurements from diagnosis to outcomes, study end, or loss to follow-up were collected. An extended Cox proportional hazards model with TSH considered as a time varying covariate was fitted for each outcome. RESULTS: 162 369 patients with hypothyroidism and 863 072 TSH measurements were included in the analysis. Compared with the reference TSH category (2-2.5 mIU/L), risk of ischaemic heart disease and heart failure increased at high TSH concentrations (>10 mIU/L) (hazard ratio 1.18 (95% confidence interval 1.02 to 1.38; P=0.03) and 1.42 (1.21 to 1.67; P<0.001), respectively). A protective effect for heart failure was seen at low TSH concentrations (hazard ratio 0.79 (0.64 to 0.99; P=0.04) for TSH <0.1 mIU/L and 0.76 (0.62 to 0.92; P=0.006) for 0.1-0.4 mIU/L). Increased mortality was observed in both the lowest and highest TSH categories (hazard ratio 1.18 (1.08 to 1.28; P<0.001), 1.29 (1.22 to 1.36; P<0.001), and 2.21 (2.07 to 2.36; P<0.001) for TSH <0.1 mIU/L, 4-10 mIU/L, and >10 mIU/L. An increase in the risk of fragility fractures was observed in patients in the highest TSH category (>10 mIU/L) (hazard ratio 1.15 (1.01 to 1.31; P=0.03)). CONCLUSIONS: In patients with a diagnosis of hypothyroidism, no evidence was found to suggest a clinically meaningful difference in the pattern of long term health outcomes (all cause mortality, atrial fibrillation, ischaemic heart disease, heart failure, stroke/transient ischaemic attack, fractures) when TSH concentrations were within recommended normal limits. Evidence was found for adverse health outcomes when TSH concentration is outside this range, particularly above the upper reference value.


Assuntos
Doenças Cardiovasculares/epidemiologia , Fraturas Ósseas/epidemiologia , Hipotireoidismo/tratamento farmacológico , Tireotropina/sangue , Tiroxina/administração & dosagem , Adulto , Idoso , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/prevenção & controle , Feminino , Fraturas Ósseas/etiologia , Fraturas Ósseas/prevenção & controle , Humanos , Hipotireoidismo/sangue , Hipotireoidismo/complicações , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Valores de Referência , Estudos Retrospectivos , Fatores de Risco , Glândula Tireoide/metabolismo , Tireotropina/metabolismo , Tireotropina/normas
17.
Chin Med J (Engl) ; 132(18): 2143-2149, 2019 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-31478926

RESUMO

BACKGROUND: Thyroid autoimmunity (TAI) is prevalent among women of reproductive age and associated with adverse pregnancy outcomes. This study aimed to investigate the association between iron nutritional status and the prevalence of TAI in women during the first trimester of pregnancy and in non-pregnant women of childbearing age. METHODS: Cross-sectional analysis of 7463 pregnant women during the first trimester of pregnancy and 2185 non-pregnant women of childbearing age nested within the sub-clinical hypothyroid in early pregnancy study, a prospective collection of pregnant and non-pregnant women's data, was conducted in Liaoning province of China between 2012 and 2015. Serum thyrotropin, free thyroxine, thyroid peroxidase antibodies (TPOAbs), thyroglobulin antibodies (TgAbs), serum ferritin, and urinary iodine were measured. Iron deficiency (ID) was defined as serum ferritin <15 µg/L and iron overload (IO) was defined as ferritin >150 µg/L. TPOAb-positive was defined as >34 U/mL and TgAb-positive was defined as >115 U/mL. Multilevel logistic regression was conducted to examine the association between TAI and different iron nutritional status after adjusting for potential confounders. RESULTS: The prevalence of isolated TPOAb-positive was markedly higher in women with ID than those without ID, in both pregnant and non-pregnant women (6.28% vs. 3.23%, χ = 10.264, P = 0.002; 6.25% vs. 3.70%, χ = 3,791, P = 0.044; respectively). After adjusting for confounders and the cluster effect of hospitals, ID remained associated with TPOAb-positive in pregnant and non-pregnant women (odds ratio [OR]: 2.111, 95% confidence interval [CI]: 1.241-3.591, P = 0.006; and OR: 1.822, 95% CI: 1.011-3.282, P = 0.046, respectively). CONCLUSION: ID was associated with a higher prevalence of isolated TPOAbs-positive, but not with isolated TgAb-positive, in both pregnant women during the first trimester of pregnancy and non-pregnant women of childbearing age, while IO was not associated with either isolated TPOAb-positive or isolated TgAb-positive. CLINICAL TRIAL REGISTRATION: ChiCTR-TRC-13003805, http://www.chictr.org.cn/index.aspx.


Assuntos
Autoimunidade/fisiologia , Ferro/deficiência , Glândula Tireoide/imunologia , Glândula Tireoide/metabolismo , Autoanticorpos/metabolismo , Estudos Transversais , Feminino , Humanos , Iodo/metabolismo , Gravidez , Prevalência , Tireoglobulina/metabolismo , Tireotropina/metabolismo , Tiroxina/metabolismo
18.
PLoS One ; 14(8): e0220240, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31442229

RESUMO

OBJECTIVE: We evaluated frequency and risk factors of delayed TSH elevation (dTSH) and investigated follow-up outcomes in the dTSH group with venous TSH (v-TSH) levels of 6-20 mU/L according to whether late preterm infants born at gestational age (GA) 35-36 weeks had risk factors. METHODS: The medical records of 810 neonates (414 boys) born at Seoul National University Hospital who had a normal neonatal screening test (NST) and underwent the first repeat venous blood test at 10-21 days post birth were reviewed. RESULTS: Seventy-three (9.0%) neonates showed dTSH, defined as a v-TSH level ≥6.0 mU/L, 12 of whom (1.5%) were started on levothyroxine medication. A multivariate-adjusted model indicated that a low birth weight (LBW <2,000 g), a congenital anomaly, and exposure to iodine contrast media (ICM) were significant predictors for dTSH (all p < 0.05). Among these 73 dTSH infants, all 5 infants with TSH levels ≥20 mU/L began levothyroxine medication, and 6 of 16 infants with v-TSH levels of 10-20 mU/L were indicated for levothyroxine, regardless of coexisting risk factors. However, only 1 of 52 infants with v-TSH levels of 6-10 mU/L who had a congenital anomaly was indicated for levothyroxine. All healthy late preterm infants, including LBW and multiple births, with v-TSH levels of 6-10 mU/L exhibited normal thyroid function. CONCLUSIONS: dTSH was detected in 9.0% and levothyroxine was indicated in 1.5% of infants born at GA 35-36 weeks, particularly those with a LBW, a congenital anomaly, or history of ICM exposure. Either levothyroxine or retesting is indicated for late preterm neonates with TSH levels ≥10 mU/L regardless of risk factors. If healthy preterm neonates show v-TSH levels of 6-10 mU/L, a second repeat test may not be necessary; however, further studies are required to set a threshold for retesting.


Assuntos
Idade Gestacional , Recém-Nascido Prematuro/metabolismo , Tireotropina/metabolismo , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez , Fatores de Risco , Tiroxina/farmacologia , Fatores de Tempo
19.
Mol Pharmacol ; 96(4): 452-462, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31399504

RESUMO

The large TSH-bound ectodomain of the thyrotropin receptor (TSHR) activates the transmembrane domain (TMD) indirectly via an internal agonist (IA). The ectodomain/TMD interface consists of a converging helix, a Cys-Cys-bridge-linked IA, and extracellular loops (ECL). To investigate the intramolecular course of molecular activation, especially details of the indirect activation, we narrowed down allosteric inhibition sites of negative allosteric modulator (NAM) by mutagenesis, homology modeling, and competition studies with positive allosteric modulator (PAM). From the inhibitory effects of NAM S37a on: 1) chimeras with swapped ectodomain, 2) stepwise N-terminal truncations, 3) distinct constitutively active mutations distributed across the hinge region and ECL, but not across the TMD, we conclude that S37a binds at the ectodomain/TMD interface, between the converging helix, ECL1, and the IA. This is also supported by the noncompetitive inhibition of PAM-C2-activation by S37a in the TSHR-TMD construct lacking the ectodomain. Mutagenesis studies on the IA and ECL were guided by our refined model of the ectodomain/TMD interface and indicate an interaction with the TSHR-specific residues E404 (preceding IA) and H478 (ECL1). At this new allosteric interaction site, NAM S37a blocks both TSH- and PAM-induced activation of the TSHR. Our refined models, mutations, and new allosteric binding pocket helped us to gain more detailed insights into the intramolecular course of TSHR activation at the ectodomain/TMD interface, including the delocalization of the converging helix and rearrangement of the conformation of IA. These changes are embedded between the ECL and cooperatively trigger active conformations of TMD. SIGNIFICANCE STATEMENT: The intramolecular activation mechanisms of the TSHR appear to be distinct from those of other G protein-coupled receptors, as the TSHR has a uniquely large N-terminal ectodomain that includes the hormone binding site and an internal agonist sequence. We present new molecular and structural insights into the interface between ectodomain and transmembrane domain in the TSHR, as well as the transfer of activation to the transmembrane domain. This knowledge is critical for understanding activation or inhibition of the receptor by allosteric ligands. We have identified a new allosteric antagonist binding pocket that is located exactly at this interface and possesses specific features that may allow the generation of potent highly TSHR-selective drugs, of potential value for the treatment of Graves' orbitopathy.


Assuntos
Receptores da Tireotropina/química , Receptores da Tireotropina/metabolismo , Tireotropina/metabolismo , Regulação Alostérica , Regulação da Expressão Gênica , Células HEK293 , Humanos , Modelos Moleculares , Mutação , Domínios Proteicos , Receptores da Tireotropina/genética , Homologia de Sequência de Aminoácidos , Transdução de Sinais
20.
Ann Endocrinol (Paris) ; 80(4): 216-224, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31400861

RESUMO

TSH (thyroid-stimulating hormone)-secreting tumors are the rarest type of pituitary tumor. The objective of this study was to describe initial presentation and follow-up in patients presenting TSH-secreting tumors and to characterize the pathological features, based on a cohort of 20 patients treated in our referral center, between 1981 and 2014. Most of the patients (75%) were female, aged around 50 years (mean: 50±13 years). Initial symptoms were hyperthyroidism (8/20) and/or tumor mass-related symptoms. Median time to diagnosis was 18 months. Biochemical hyperthyroidism was found in 15 patients. Most of the tumors were macroadenomas (75%) and 30% were invasive. Seventeen patients underwent transsphenoidal surgery. All tumors expressed TSH, with>50% positive cells. Eleven were monohormonal and 6 plurihormonal, expressing ßTSH plus growth hormone (GH) and/or prolactin (PRL). Both subtypes showed high expression of Pit-1 and SSTR2A somatostatin receptors. SSTR5 was slightly expressed in the plurihormonal subtype. Ki-67 index was elevated (≥3%) in only one tumor. Signs of hyperthyroidism were more frequent in the plurihormonal than in the monohormonal subtype. At final follow-up (median: 34.79±66.7 months), 75% of the patients were in complete remission after surgery; persistent hyperthyroidism was controlled by somatostatin analogs, alone (n=3) or associated to radiotherapy (n=1). The multidisciplinary approach promoted early diagnosis and control of hyperthyroidism by neurosurgical treatment, associated to somatostatin analogs or not. Clinical/pathological correlations highlighted the variations in immune profiles and in clinical and biological symptoms.


Assuntos
Adenoma , Neoplasias Hipofisárias , Tireotropina/metabolismo , Adenoma/diagnóstico , Adenoma/metabolismo , Adenoma/patologia , Adenoma/terapia , Adulto , Idoso , Feminino , França , História do Século XX , História do Século XXI , Humanos , Hipertireoidismo/diagnóstico , Hipertireoidismo/patologia , Hipertireoidismo/terapia , Masculino , Pessoa de Meia-Idade , Neoplasias Hipofisárias/diagnóstico , Neoplasias Hipofisárias/metabolismo , Neoplasias Hipofisárias/patologia , Neoplasias Hipofisárias/terapia , Estudos Retrospectivos , Somatostatina/análogos & derivados , Somatostatina/uso terapêutico
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