Prevalencia de hipertirotropinemia neonatal comoindicador de deficiencia de yodo en la provincia de La Pampa: un análisis epidemiológico / Prevalence of high neonatal thyroid stimulating hormone levels as an indicator of iodine deficiency in the province of La Pampa: An epidemiological analysis

Introducción. El yodo desempeña un rol fundamental en el metabolismo, el crecimiento y el desarrollo humano. Durante el embarazo y la infancia, la demanda de este micronutriente aumenta considerablemente. La tirotropinemia neonatal (TSHn) aumentada, definida como TSHn ≥5 mUI/l, es un marcador que señala la deficiencia de yodo en una población cuando su prevalencia supera el 3 %. Objetivo. Determinar la prevalencia de TSHn ≥ 5 en La Pampa durante el período 2021-2022, analizar su correlación con diferentes variables y compararla con datos de una cohorte histórica. Población y métodos. Estudio transversal, de diseño descriptivo-analítico, sobre una población de neonatos nacidos en las cinco zonas sanitarias de la provincia de La Pampa durante los años 2021 y 2022. Resultados. De los 5778 neonatos evaluados, el 9,6 % presentó niveles de TSHn ≥5 mUI/l. El 70,4 % de estas mediciones fueron realizadas después del tercer día de vida. No se observaron diferencias significativas en la frecuencia de niveles elevados de TSHn según el año de nacimiento, peso al nacer o días hasta la extracción. Se registró una mayor prevalencia en el sexo masculino (10,6 % versus 8,5 %; p = 0,007) y entre los neonatos nacidos a término (9,8 % versus 6,6 %; p = 0,02). La prevalencia de hipertirotropinemia fue superior a la observada en una cohorte de 2001-2002. Conclusiones. La prevalencia de hipertirotropinemia neonatal en La Pampa durante los años 2021 y 2022 fue del 9,6 %, lo que indica un estado de deficiencia leve de yodo en la provincia, superior al reportado hace dos décadas.

Introduction. Iodine plays a key role in human metabolism, growth, and development. During pregnancy and childhood, the demand for this micronutrient increases notably. Increased neonatal thyroid stimulating hormone (nTSH) levels, defined as nTSH ≥ 5 mIUL, are a marker of iodine deficiency in a population if its prevalence is higher than 3%.Objective. To establish the prevalence of nTSH ≥ 5 in La Pampa in the 2021­2022 period, analyze its correlation with different variables, and compare it with data from a historical cohort.Population and methods. Cross-sectional, descriptive-analytical study in a population of newborn infants born in the 5 health regions of the province of La Pampa in 2021 and 2022. Results. Of  the  5778  assessed  newborn  infants,  9.6%  had  nTSH  levels  ≥  5  mIU/L. It was reported that 70.4% of these measurements were done after the third day of life. No significant differences were observed in the frequency of high nTSH levels by year of birth, birth weight, or days until samplecollection.A higher prevalence was observed among male infants (10.6% versus 8.5%; p = 0.007) and term infants (9.8% versus 6.6%; p = 0.02). The prevalence of high TSH levels was superior to that observed in the 2001­2002 cohort. Conclusions. The  prevalence of high nTSH levels in La Pampa during 2021 and 2022 was 9.6%, suggesting the presence of mild iodine deficiency in the population of this province, higher that what  had been reported 2 decades ago.

Associations of TSH, free T3, free T4, and conversion ratio with incident hypertension: results from the prospective Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).

Objective: To evaluate the association of TSH, free T3 (FT3), free T4 (FT4), and conversion (FT3:FT4) ratio values with incident hypertension. Materials and methods: The study included data from participants of the ELSA-Brasil study without baseline hypertension. Serum TSH, FT4 and FT3 levels, and FT3:FT4 ratio values were assessed at baseline, and incident hypertension (defined by blood pressure levels ≥ 140/90 mmHg) was estimated over a median of 8.2 years of follow-up. The risk of incident hypertension was evaluated considering a 1-unit increase in TSH, FT4, FT3, and conversion ratio values and after dividing these variables into quintiles for further analysis using Poisson regression with robust variance. The results are presented as relative risks (RR) and 95% confidence intervals (CIs) before and after adjustment for multiple variables. Results: The primary analysis incorporated data from 5,915 euthyroid individuals, and the secondary analysis combined data from all euthyroid individuals, 587 individuals with subclinical hypothyroidism, and 31 individuals with subclinical hyperthyroidism. The rate of incident hypertension was 28% (95% CI: 27%-29.3%). The FT4 levels in the first quintile (0.18-1.06 ng/dL) were significantly associated with incident hypertension (RR: 1.03, 95% CI: 1.01-1.06) at follow-up. The association between FT4 levels in the first quintile and incident hypertension was also observed in the analysis of combined data from euthyroid individuals and participants with subclinical thyroid dysfunction (RR: 1.04, 95% CI: 1.01-1.07). The associations were predominantly observed with systolic blood pressure levels in euthyroid individuals. However, in the combined analysis incorporating euthyroid participants and individuals with subclinical thyroid dysfunction, the associations were more pronounced with diastolic blood pressure levels. Conclusion: Low FT4 levels may be a mild risk factor for incident hypertension in euthyroid individuals and persons with subclinical thyroid dysfunction.

Prevalence of high neonatal thyroid stimulating hormone levels as an indicator of iodine deficiency in the province of La Pampa: An epidemiological analysis. / Prevalencia de hipertirotropinemia neonatal como indicador de deficiencia de yodo en la provincia de La Pampa: un análisis epidemiológico.

Introduction. Iodine plays a key role in human metabolism, growth, and development. During pregnancy and childhood, the demand for this micronutrient increases notably. Increased neonatal thyroid stimulating hormone (nTSH) levels, defined as nTSH ≥ 5 mIU/L, are a marker of iodine deficiency in a population if its prevalence is higher than 3%. Objective. To establish the prevalence of nTSH ≥ 5 in La Pampa in the 2021-2022 period, analyze its correlation with different variables, and compare it with data from a historical cohort. Population and methods. Cross-sectional, descriptive-analytical study in a population of newborn infants born in the 5 health regions of the province of La Pampa in 2021 and 2022. Results. Of the 5778 assessed newborn infants, 9.6% had nTSH levels ≥ 5 mIU/L. It was reported that 70.4% of these measurements were done after the third day of life. No significant differences were observed in the frequency of high nTSH levels by year of birth, birth weight, or days until sample collection. A higher prevalence was observed among male infants (10.6% versus 8.5%; p = 0.007) and term infants (9.8% versus 6.6%; p = 0.02). The prevalence of high TSH levels was superior to that observed in the 2001-2002 cohort. Conclusions. The prevalence of high nTSH levels in La Pampa during 2021 and 2022 was 9.6%, suggesting the presence of mild iodine deficiency in the population of this province, higher that what had been reported 2 decades ago.

Introducción. El yodo desempeña un rol fundamental en el metabolismo, el crecimiento y el desarrollo humano. Durante el embarazo y la infancia, la demanda de este micronutriente aumenta considerablemente. La tirotropinemia neonatal (TSHn) aumentada, definida como TSHn ≥5 mUI/l, es un marcador que señala la deficiencia de yodo en una población cuando su prevalencia supera el 3 %. Objetivo. Determinar la prevalencia de TSHn ≥ 5 en La Pampa durante el período 2021-2022, analizar su correlación con diferentes variables y compararla con datos de una cohorte histórica. Población y métodos. Estudio transversal, de diseño descriptivo-analítico, sobre una población de neonatos nacidos en las cinco zonas sanitarias de la provincia de La Pampa durante los años 2021 y 2022. Resultados. De los 5778 neonatos evaluados, el 9,6 % presentó niveles de TSHn ≥5 mUI/l. El 70,4 % de estas mediciones fueron realizadas después del tercer día de vida. No se observaron diferencias significativas en la frecuencia de niveles elevados de TSHn según el año de nacimiento, peso al nacer o días hasta la extracción. Se registró una mayor prevalencia en el sexo masculino (10,6 % versus 8,5 %; p = 0,007) y entre los neonatos nacidos a término (9,8 % versus 6,6 %; p = 0,02). La prevalencia de hipertirotropinemia fue superior a la observada en una cohorte de 2001-2002. Conclusiones. La prevalencia de hipertirotropinemia neonatal en La Pampa durante los años 2021 y 2022 fue del 9,6 %, lo que indica un estado de deficiencia leve de yodo en la provincia, superior al reportado hace dos décadas.

Resposta Vascular da Triiodotironina sobre Anéis de Aortas Isoladas: Contribuição de Mecanismos Redox / Vascular Response of Triiodothyronine on Isolated Aortic Rings: Contribution of Redox Mechanisms

Resumo Fundamento A disfunção vascular constitui a etiologia de diversas doenças, incluindo infarto do miocárdio e hipertensão, diante da ruptura da homeostase oxi-redutiva ("redox"), desempenhando um papel no desequilíbrio do mecanismo de controle vasomotor. Nosso grupo demonstrou anteriormente que os hormônios tireoidianos melhoram a sinalização da angiogênese, exercendo efeitos protetores sobre o tecido aórtico de ratos infartados. Objetivos Investigar o papel da triiodotironina (T3) na resposta vascular, explorando seus efeitos em aortas isoladas e a presença de mecanismos redox vasculares. Métodos Anéis aórticos isolados (endotélio intacto e desnudado) pré-contraídos com fenilefrina foram incubados com T3 (10-8, 10-7, 10-6, 10-5 e 10-4 M) e a tensão foi registrada usando um transdutor de deslocamento de força acoplado a um sistema de coleta. Para avaliar o envolvimento do estresse oxidativo, os anéis aórticos foram pré-incubados com T3 e posteriormente submetidos a um sistema de geração de espécies reativas de oxigênio (ROS) in vitro. O nível de significância adotado na análise estatística foi de 5%. Resultados A T3 (10-4 M) promoveu o vasorrelaxamento dos anéis aórticos pré-contraídos com fenilefrina em endotélio intacto e desnudado. Os anéis aórticos pré-incubados na presença de T3 (10-4 M) também mostraram diminuição da vasoconstrição provocada pela fenilefrina (1 µM) em preparações de endotélio intacto. Além disso, o efeito vasorrelaxante da T3 (10-4 M) persistiu em anéis aórticos pré-incubados com éster metílico de NG-nitro-L-arginina (L-NAME, 10 µM), um inibidor inespecífico da NO sintase (NOS). Por fim, a T3 (10-4 M) exibiu, in vitro, um papel antioxidante ao reduzir a atividade da NADPH oxidase e aumentar a atividade da SOD nos homogenatos aórticos. Conclusão A T3 exerce efeitos dependentes e independentes de endotélio, o que pode estar relacionado ao seu papel na manutenção da homeostase redox.

Abstract Background Vascular dysfunction constitutes the etiology of many diseases, such as myocardial infarction and hypertension, with the disruption of redox homeostasis playing a role in the imbalance of the vasomotor control mechanism. Our group previously has shown that thyroid hormones exert protective effects on the aortic tissue of infarcted rats by improving angiogenesis signaling. Objective Investigate the role of triiodothyronine (T3) on vascular response, exploring its effects on isolated aortas and whether there is an involvement of vascular redox mechanisms. Methods Isolated aortic rings (intact- and denuded-endothelium) precontracted with phenylephrine were incubated with T3 (10-8, 10-7, 10-6, 10-5, and 10-4 M), and tension was recorded using a force-displacement transducer coupled with an acquisition system. To assess the involvement of oxidative stress, aortic rings were preincubated with T3 and subsequently submitted to an in vitro reactive oxygen species (ROS) generation system. The level of significance adopted in the statistical analysis was 5%. Results T3 (10-4 M) promoted vasorelaxation of phenylephrine precontracted aortic rings in both intact- and denuded-endothelium conditions. Aortic rings preincubated in the presence of T3 (10-4 M) also showed decreased vasoconstriction elicited by phenylephrine (1 µM) in intact-endothelium preparations. Moreover, T3 (10-4 M) vasorelaxation effect persisted in aortic rings preincubated with NG-nitro-L-arginine methylester (L-NAME, 10 µM), a nonspecific NO synthase (NOS) inhibitor. Finally, T3 (10-4 M) exhibited, in vitro, an antioxidant role by reducing NADPH oxidase activity and increasing SOD activity in the aorta's homogenates. Conclusion T3 exerts dependent- and independent-endothelium vasodilation effects, which may be related to its role in maintaining redox homeostasis.

Homeostatic status of thyroid hormones and brain water movement as determinant factors in biology of cerebral gliomas: a pilot study using a bioinformatics approach.

Introduction: The expression and localization of the water channel transporters, aquaporins (AQPs), in the brain are substantially modified in gliomas during tumorigenesis, cell migration, edema formation, and resolution. We hypothesized that the molecular changes associated with AQP1 and AQP4 in the brain may potentially be anticancer therapeutic targets. To test this hypothesis, a bioinformatics analysis of publicly available data from international consortia was performed. Methods: We used RNA-seq as an experimental strategy and identified the number of differential AQP1 and AQP4 transcript expressions in glioma tissue compared to normal brain tissue. Results: AQPs genes are overexpressed in patients with glioma. Among the glioma subtypes, AQP1 and AQP4 were overexpressed in astrocytoma (low-grade glioma) and classical (high-grade glioma). Overall survival analysis demonstrated that both AQP genes can be used as prognostic factors for patients with low-grade glioma. Additionally, we observed a correlation between the expression of genes involved in the tyrosine and thyroid hormone pathways and AQPs, namely: PNMT, ALDH1A3, AOC2, HGDATP1B1, ADCY5, PLCB4, ITPR1, ATP1A3, LRP2, HDAC1, MED24, MTOR, and ACTB1 (Spearman's coefficient = geq 0.20 and p-value = ≤ 0.05). Conclusion: Our findings indicate that the thyroid hormone pathways and AQPs 1 and 4 are potential targets for new anti-tumor drugs and therapeutic biomarkers for malignant gliomas.

The effect of different levothyroxine administration regimens on thyroid hormone levels: a systematic review, pairwise, and network meta-analysis.

INTRODUCTION: This systematic review aimed to compare the effect of alternative levothyroxine administration regimens on thyroid hormone levels and patient-reported outcomes (PROs) among adults with hypothyroidism. METHODS: We searched PubMed, Embase, CENTRAL, CINAHL, LILACS, SciELO, Scopus, Web of Science, OpenGrey, ProQuest, ClinicalTrials.gov, and ICTRP from inception to May/2023 for randomized controlled trials (RCTs). We assessed the risk of bias with Cochrane Risk of Bias 2.0 tool. We analyzed TSH levels by pairwise and network meta-analyses (NMA). The FT4 levels and PROs were qualitatively assessed. RESULTS: We included 14 RCTs (906 participants) comparing different regimens, as bedtime vs. before breakfast. A total of 12 RCTs were at high risk of bias. Seven RCTs were included in the TSH meta-analysis, where the mean difference (MD) and 95% confidence interval (CI) were as follows: bedtime vs before breakfast (4 RCTs) 0.69 (-1.67-3.04), I2 = 92%, very low certainty evidence; weekly dose vs before breakfast (2 RCTs) 1.68 (0.94-2.41), I2 = 0%, low certainty evidence; and at breakfast vs before breakfast (1 RCT) 0.65 (-1.11-2.41), very low certainty evidence. The NMA showed no evidence of differences in TSH level with different regimens. CONCLUSION: The evidence is insufficient to determine the most effective levothyroxine administration regimen for hypothyroidism. SYSTEMATIC REVIEW REGISTRATION: PROSPERO - CRD42021279375.

Associations of TSH, free T3, free T4, and conversion ratio with incident hypertension: results from the prospective Brazilian Longitudinal Study of Adult Health (ELSA-Brasil)

ABSTRACT Objective: To evaluate the association of TSH, free T3 (FT3), free T4 (FT4), and conversion (FT3:FT4) ratio values with incident hypertension. Materials and methods: The study included data from participants of the ELSA-Brasil study without baseline hypertension. Serum TSH, FT4 and FT3 levels, and FT3:FT4 ratio values were assessed at baseline, and incident hypertension (defined by blood pressure levels ≥ 140/90 mmHg) was estimated over a median of 8.2 years of follow-up. The risk of incident hypertension was evaluated considering a 1-unit increase in TSH, FT4, FT3, and conversion ratio values and after dividing these variables into quintiles for further analysis using Poisson regression with robust variance. The results are presented as relative risks (RR) and 95% confidence intervals (CIs) before and after adjustment for multiple variables. Results: The primary analysis incorporated data from 5,915 euthyroid individuals, and the secondary analysis combined data from all euthyroid individuals, 587 individuals with subclinical hypothyroidism, and 31 individuals with subclinical hyperthyroidism. The rate of incident hypertension was 28% (95% CI: 27%-29.3%). The FT4 levels in the first quintile (0.18-1.06 ng/dL) were significantly associated with incident hypertension (RR: 1.03, 95% CI: 1.01-1.06) at follow-up. The association between FT4 levels in the first quintile and incident hypertension was also observed in the analysis of combined data from euthyroid individuals and participants with subclinical thyroid dysfunction (RR: 1.04, 95% CI: 1.01-1.07). The associations were predominantly observed with systolic blood pressure levels in euthyroid individuals. However, in the combined analysis incorporating euthyroid participants and individuals with subclinical thyroid dysfunction, the associations were more pronounced with diastolic blood pressure levels. Conclusion: Low FT4 levels may be a mild risk factor for incident hypertension in euthyroid individuals and persons with subclinical thyroid dysfunction.

Avaliação da mortalidade associada ao status tireoidiano em uma coorte de pessoas idosas eutireoidianas de ambulatório de geriatria em hospital universitário / Assessment of mortality associated with thyroid status in a cohort of euthyroid older adults from a geriatric outpatient clinic at a university hospital

Resumo Objetivo Avaliar associações entre a média da tireotropina (TSH) e tiroxina livre (T4L) mantida durante follow-up, e mortalidade em pacientes idosos eutireoidianos definidos de acordo com a faixa de referência específica para a idade (FR-e) do TSH. Método Coorte retrospectiva tipo análise de sobrevivência incluindo pacientes idosos eutireoidianos acompanhados no ambulatório de hospital universitário entre 2010 e 2013. Todos os participantes haviam sido avaliados quanto ao risco de incapacidade funcional como critério para admissão nesse ambulatório. As médias dos valores de TSH e T4L foram calculadas através das dosagens obtidas no período de acompanhamento. Cada FR-e de TSH foi dividida em quatro partes iguais, considerando níveis mais baixos como variável de exposição (≤1,75 mUI/L para <80 e ≤2,0 mUI/L para ≥80 anos). Os níveis de T4L foram dicotomizados em duas categorias (< e ≥1,37 ng/dL). O desfecho foi o tempo até a morte. A regressão de risco proporcional de Cox foi empregada para estimar a hazard ratio (HR) e o intervalo de confiança (IC) de 95% Resultados 285 participantes (73% mulheres, idade média =80,4 anos) seguidos pela mediana de 5,7 anos (IQR =3,7-6,4; máximo =7), sendo que 114 faleceram. Após o modelo final ajustado, a mortalidade esteve associada ao TSH no limite inferior (HR=1,7; IC=1,1-2,7; p=0,016) e ao T4L mais elevado. (HR=2,0; IC=1,0-3,8; p=0,052). Conclusão Níveis médios de T4L mais altos e de TSH mais baixos foram associados ao risco de morte em coorte de idosos eutireoidianos usando FR-e de TSH.

Abstract Objective To assess the associations between the mean thyrotropin (TSH) and mean free thyroxine (FT4), detected during follow-up, and mortality in a group of older euthyroid patients according to age-specific reference range (as-RR) for TSH. Method Retrospective survival analysis cohort including euthyroid elderly patients who were being monitored at the outpatient clinic of a university hospital from 2010 to 2013. All participants had been assessed for the risk of functional disability as a criterion for admission to this outpatient clinic. Mean TSH and FT4 values were calculated using hormone dosages obtained during the follow-up period. Each as-RR for TSH was divided into four equal parts, considering the lower levels as the main exposure variable (≤1.75 mlU/L for <80, and ≤2.0 mlU/L for ≥80 years). FT4 levels were explored according to two categories (< e ≥1.37 ng/dL). The outcome was time to death. We used Cox proportional hazard regression to estimate the hazard ratio (HR) and 95% confidence interval (CI). Results 285 participants (73% females, mean age =80.4 years) followed by a median of 5.7 years (IQR =3.7-6.4; maximum =7), of which 114 died. After the adjusted final model, mortality was associated with the lowest mean TSH (HR=1.7; CI=1.1-2.7; p=0.016) and with the upper mean of FT4 (HR=2.0; CI=1.0-3.8; p=0.052). Conclusions Higher FT4 and lower TSH mean levels were associated with risk of death in a cohort of euthyroid older adults using an as-RR of TSH.

Síndrome metabólico e hipotiroidismo: un estudio transversal en una población ecuatoriana

Introducción: el síndrome metabólico y el hipotiroidismo son condiciones muy frecuentes y a menudo superpuestas. Ambos son precursores bien establecidos de la enfermedad cardiovascular aterogénica. Objetivo: evaluar la asociación entre el hipotiroidismo y el síndrome metabólico en pacientes que asisten a la consulta de medicina interna del Hospital IESS de Riobamba, Ecuador. Metodología: se realizó una investigación de tipo descriptiva, correlacional con un diseño no experimental de corte transversal desde enero de 2022 hasta julio de 2023. Se incluyeron 985 sujetos de ambos sexos, mayores de 25 años. A todos los pacientes se les realizó un exhaustivo examen físico y se tomaron muestras de sangre para la realización de pruebas bioquímicas y hormonales. Resultados: 84,97% de los participantes eran eutiroideos, 1,93% presentaron hipotiroidismo manifiesto y 4,97% hipotiroidismo subclínico, mientras que 32,99% tenían síndrome metabólico. Se encontraron diferencias significativas en la edad, peso, circunferencia de cintura, colesterol total, LDL colesterol, triglicéridos, glucosa postpandrial y HOMA-IR entre los sujetos con hipotiroidismo manifiesto y los eutiroideos (p<0,05). Se observó una correlación positiva entre la TSH y todos los componentes del síndrome metabólico (p<0,05). La prevalencia de síndrome metabólico fue significativamente mayor en los sujetos con hipotiroidismo manifiesto (p < 0,05) que en los demás grupos. Se observó que los niveles de T4L (OR 8,82; IC 95% 1,56-49,8) y TSH (OR 1,61; IC 95% 1,19-2,18) son factores de riesgo para el desarrollo de síndrome metabólico. Conclusión: el hipotiroidismo y el síndrome metabólico están altamente asociados. Es recomendable que los sujetos con hipotiroidismo sean examinados para detectar síndrome metabólico y viceversa. La evaluación de la función tiroidea en pacientes con este síndrome puede ayudar a identificar y prevenir el riesgo de eventos cardiovasculares y cerebrovasculares.

Introduction: Metabolic syndrome and hypothyroidism are widespread and often overlapping conditions. Both are well-established precursors of atherogenic cardiovascular disease. Objective: To evaluate the association between hypothyroidism and metabolic syndrome in patients attending the internal medicine consultation at the IESS Hospital in Riobamba, Ecuador. Methodology: A descriptive, correlational research study was conducted with a non-experimental cross-sectional design from January 2022 to July 2023. Nine hundred eighty-five subjects of both sexes and over 25 years of age, were included. All patients underwent a thorough physical examination and blood samples were taken for biochemical and hormonal tests. Results: Eighty-four-point ninety-seven percent of the participants were euthyroid, 1.93% presented overt hypothyroidism, 4.97% had subclinical hypothyroidism, and 32.99% had metabolic syndrome. Significant differences in age, weight, waist circumference, total cholesterol, LDL cholesterol, triglycerides, postprandial glucose, and HOMA-IR were found between subjects with manifest hypothyroidism and euthyroid subjects (p<0.05). A positive correlation was observed between TSH and all components of the metabolic syndrome (p<0.05). The prevalence of metabolic syndrome was significantly higher in subjects with overt hypothyroidism (p < 0.05) than in the other groups. It was observed that the levels of FT4 (OR 8.82; 95% CI 1.56-49.8) and TSH (OR 1.61; 95% CI 1.19-2.18) were risk factors for the development of the metabolic syndrome. Conclusion: Hypothyroidism and metabolic syndrome are highly associated. It is recommended that subjects with hypothyroidism be screened for metabolic syndrome and vice versa. Evaluation of thyroid function in patients with this syndrome can help identify and prevent the risk of cardiovascular and cerebrovascular events.

Exposición al Dicloro Difenil Tricloroetano y perfil tiroideo durante el embarazo: revisión sistemática y meta-análisis / Dichlorodiphenyltrichloroethane pesticide exposure and thyroid profile during pregnancy: systematic review and meta-analysis

Resumen Objetivo: Evaluar la asociación entre la exposición al p,p´-DDT y p,p´-DDE con la disrupción tiroidea durante el embarazo a través de un metaanálisis. Material y métodos: Se realizó una revisión sistemática y un meta-análisis basado en la declaración PRISMA (Preferred Reporting Items for Systematic Reviews and MetaAnalysis). El protocolo de esta revisión se registró ante el International Prospective Register of Systematic Reviews (PROSPERO) con el folio de identificación: CRD42022324797. Se llevó a cabo una búsqueda en las bases de datos electrónicas PubMed y Web of Science para identificar los estudios elegibles publicados en inglés y español hasta el 2 de enero de 2022. Mediante meta-análisis de efectos aleatorios, se estimó un coeficiente de regresión beta (β) combinado, por cada hormona del perfil tiroideo, a partir de los β publicados de cada estudio y sus intervalos de confianza del 95% (IC del 95%). Resultados: Se incluyeron ocho estudios de los cuales solamente tres reportaron biomarcadores de exposición a p,p'-DDT, por lo que no fue posible conducir metaanálisis para evaluar la relación entre este compuesto y las hormonas del perfil tiroideo. La exposición a p,p'-DDE se asoció con un ligero incremento en los niveles de TSH (β combinada= 0.05; IC95%= -0.01. 0.12) y T3 total (β combinada= 0.02; IC95%= -0.05, 0.09), pero inversamente con los niveles de la T4 total (β combinada= -0.003; IC 95%= -0.05, 0.05) y T4 libre (β combinada= -0.01; IC95%= -0.03, 0.01), aunque ninguno de estos hallazgos fue estadísticamente significativo. Conclusiones: La evidencia disponible a la fecha aún es limitada como para emitir una conclusión sobre la asociación entre las variables de interés. Dado que pequeños cambios en la homeóstasis tiroidea de mujeres embarazadas podrían tener consecuencias en el desarrollo fetal, es necesario seguir generando evidencia al respecto.

Abstract Objective: Evaluate the association between p,p´-DDT and p,p´-DDE exposure with thyroid disruption during pregnancy through meta-analysis. Material and methods: We performed a systematic review and meta-analysis based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). The protocol of this review was registered in PROSPERO with the identification sheet: CRD42022324797. We conduct systematic searches in PubMed and Web of Science electronic databases to identify eligible studies published in English and Spanish up to January 2, 2022. Using random-effects meta-analysis, a beta regression coefficient was estimated (β) pooled, for each hormone of the thyroid profile, from the β published in each study and their 95% confidence intervals (95% CI). Results: Eight studies were included, of which only three reported biomarkers of exposure to p,p'-DDT, so it was not possible to conduct a meta-analysis to assess the relationship between this compound and hormones in the thyroid profile. Exposure to p,p'-DDE was associated with a slight increase in TSH (pooled β= 0.05; 95% CI= -0.01, 0.12) and total T3 (pooled β= 0.02; 95% CI= -0.05, 0.09) levels , but inversely with total T4 (β pooled= -0.003; 95% CI= -0.05, 0.05) and free T4 (β pooled= -0.01; 95% CI= -0.03, 0.01) levels, although neither of these findings was statistically significant. Conclusions: The evidence available to date is still limited to draw a conclusion on the association between the variables of interest. Since small changes in thyroid homeostasis in pregnant women could have consequences on fetal development, it is necessary to continue generating evidence in this regard.

Understanding the Relationship between Nonalcoholic Fatty Liver Disease and Thyroid Disease.

The prevalence of hypothyroidism in patients with nonalcoholic fatty liver disease (NAFLD) is high (22.4%). Thyroid hormones (THs) regulate many metabolic activities in the liver by promoting the export and oxidation of lipids, as well as de novo lipogenesis. They also control hepatic insulin sensitivity and suppress hepatic gluconeogenesis. Because of its importance in lipid and carbohydrate metabolism, the involvement of thyroid dysfunction in the pathogenesis of NAFLD seems plausible. The mechanisms implicated in this relationship include high thyroid-stimulating hormone (TSH) levels, low TH levels, and chronic inflammation. The activity of the TH receptor (THR)-ß in response to THs is essential in the pathogenesis of hypothyroidism-induced NAFLD. Therefore, an orally active selective liver THR-ß agonist, Resmetirom (MGL-3196), was developed, and has been shown to reduce liver fat content, and as a secondary end point, to improve nonalcoholic steatohepatitis. The treatment of NAFLD with THR-ß agonists seems quite promising, and other agonists are currently under development and investigation. This review aims to shine a light on the pathophysiological and epidemiological evidence regarding this relationship and the effect that treatment with THs and selective liver THR-ß agonists have on hepatic lipid metabolism.

Manejo del paciente con Hipertiroidismo en consulta externa de la Unidad Técnica de Endocrinología del Hospital Carlos Andrade Marín / Management of the patient with hyperthyroidism in the outpatient clinic of the Technical Unit of Endocrinology of the Endocrinology Technical Unit of the Carlos Andrade Marín Hospital

El hipertiroidismo es un trastorno caracterizado por el exceso de hormonas tiroideas. El déficit de yodo es un factor clave en dicha patología y en lugares con suficiencia del mismo se asocian a au-toinmunidad tiroidea. La prevalencia de hipertiroidismo mani-fiesto varía del 0,2% al 1,3% en áreas con suficiencia de yodo, sin embargo, esto puede variar en cada país por diferencias en umbrales de diagnóstico, sensibilidad de ensayo y población se-leccionada. Un reporte de The Third National Health and Nutri-tion Examination Survey (NHANES III) mostró que el hiperti-roidismo manifiesto se presenta en 0,7% de la población general e hipertiroidismo subclínico en el 1,7%1,2.En incidencia, la patología se asocia con la suplementación de yodo, con la mayor frecuencia en áreas de deficiencias, por au-mento de nódulos tiroideos en la población anciana, teniendo a regiones de áreas montañosas como América del Sur, África Central y suroeste de Asia dentro de este grupo. Un meta aná-lisis de estudios europeos mostró una incidencia general de 50 casos por 100000 personas/años1. En Ecuador, según los datos del Instituto Nacional de Estadísticas y Censos (INEC) del 2017, se reportaron 157 casos de hipertiroidismo, de los cuales la En-fermedad de Graves (EG) fue la causa más común, seguida por el bocio multinodular tóxico (BMNT) y finalmente el adenoma tóxico (AT) con una incidencia de 61 %, 24 % y 14 % respecti-vamente3.Los pacientes con esta patología tienen aumento de riesgo com-plicaciones cardiovasculares y mortalidad por todas las causas, siendo falla cardíaca uno de sus principales desenlaces, así el diagnóstico precoz evita estos eventos, principalmente en pobla-ción de edad avanzada.El presente protocolo se ha realizado para un correcto trata-miento de esta patología en el Hospital de Especialidades Carlos Andrade Marín (HECAM).

Hyperthyroidism is a disorder characterized by an excess of thyroid hormones. Iodine deficiency is a key factor in this pa-thology and in places with iodine deficiency it is associated with thyroid autoimmunity. The prevalence of overt hyperthyroidism varies from 0,2% to 1,3% in iodine-sufficient areas; however, this may vary from country to country due to differences in diag-nostic thresholds, assay sensitivity, and selected population. A report from The Third National Health and Nutrition Examina-tion Survey (NHANES III) showed that overt hyperthyroidism occurs in 0,7% of the general population and subclinical hyper-thyroidism in 1,7%1,2.In incidence, the pathology is associated with iodine supplemen-tation, with the highest frequency in areas of deficiencies, due to increased thyroid nodules in the elderly population, having regions of mountainous areas such as South America, Central Africa and Southwest Asia within this group. A meta-analysis of European studies showed an overall incidence of 50 cases per 100000 person/years1. In Ecuador, according to data from the National Institute of Statistics and Census (INEC) in 2017, 157 cases of hyperthyroidism were reported, of which, Graves' di-sease (GD) was the most common cause, followed by toxic mul-tinodular goiter (BMNT) and finally toxic adenoma (TA) with an incidence of 61 %, 24 % and 14 % respectively3.Patients with this pathology have an increased risk of cardiovas-cular complications and all-cause mortality, with heart failure being one of the main outcomes, so early diagnosis avoids these events, mainly in the elderly population.The present protocol has been carried out for the correct treat-ment of this pathology at the Carlos Andrade Marín Specialties Hospital (HECAM).

Thyroid axis participates in high-temperature-induced male sex reversal through its activation by the stress response.

Environmental changes alter the sex fate in about 15% of vertebrate orders, mainly in ectotherms such as fish and reptiles. However, the effects of temperature changes on the endocrine and molecular processes controlling gonadal sex determination are not fully understood. Here, we provide evidence that thyroid hormones (THs) act as co-players in heat-induced masculinization through interactions with the stress axis to promote testicular development. We first demonstrated that the thyroid axis (through thyroid-related genes and T3 levels) is highly active in males during the gonadal development in medaka (Oryzias latipes). Similarly, T3 treatments promoted female-to-male sex reversal in XX embryos. Subsequently, embryonic exposure to temperature-induced stress up-regulated the genes related to the thyroid and stress axes with a final increase in T3 levels. In this context, we show that blocking the stress axis response by the loss of function of the corticotropin-releasing hormone receptors suppresses thyroid-stimulating hormone expression, therefore, heat-induced activation of the thyroid axis. Thus, our data showed that early activation of the stress axis and, in consequence, the TH axis, too, leaves us with that both being important endocrine players in inducing female-to-male reversal, which can help predict possible upcoming physiological impacts of global warming on fish populations.

Quantitative proteomic profile analysis of thyroid dysfunction effects on seminal vesicles and repercussions on male fertility.

Hypothyroidism and thyrotoxicosis are associated with male reproductive disorders, but little is known about the influence of the thyroid hormone milieu on seminal vesicle (SV) function and metabolism. In this sense, we investigated the effects of hypothyroidism and thyrotoxicosis induced in adulthood Wistar male rats on SV function and identified new thyroid hormone targets on male reproduction regulation using novel proteomic approaches. Hypothyroidism reduces SV size and seminal fluid volume, which are directly associated with low testosterone and estradiol levels, while thyrotoxicosis increases Esr2 and Dio1 expression in the SV. We found 116 differentially expressed proteins. Hypothyroidism reduces the expression of molecular protein markers related to sperm viability, capacitation and fertilization, protection against oxidative stress and energetic metabolism in SV, while it increases the expression of proteins related to tissue damage. In conclusion, thyroid dysfunction in the adult phase impairs several morphological, molecular and functional characteristics of SV.

The memory impairment by hypothyroidism in mice is dependent on time-of-day and sex.

Hypothyroidism is an endocrine-metabolic disorder, and as such it compromises a wide range of physiological functions. Memory deficits and, the most recently described, circadian rhythm disruption are among the impairments caused by thyroid dysfunctions. However, although highly likely, there is no evidence connecting these two effects of hypothyroidism. Here, we hypothesized the time-of-day interferes with the memory deficit caused by hypothyroidism. C57BL/6 J mice from both sexes were subjected to novel object recognition (NOR) task during the rest and active phases, corresponding to ZT 2-4 and 14-16, respectively (ZT: Zeitgeber time; ZT 0: lights on at 07:00 am). First, we showed that neither sex nor ZT altered object recognition memory (ORM) in euthyroid mice. Next, animals were divided into control (euthyroid) and hypothyroid [induced with methimazole (0.01%) and perchlorate (0.1%) treatment in the drinking water for 21 days] groups. Under euthyroid conditions, male and female mice recognized the novel object regardless of the time-of-day. However, hypothyroidism impaired ORM at rest phase (ZT 2-4) in both sexes. Surprisingly, in the active phase (ZT 14-16), the hypothyroid males performed the NOR, though a longer time to execute the task was required. In contrast, female hypothyroid mice showed a greater impairment in ORM. Our results suggest that hypothyroidism may disrupt the circadian rhythm in brain areas related to mnemonic processes since in euthyroid condition ORM is not affected by the time-of-day. Furthermore, our findings in an animal model indicate a pronounced deleterious effect of hypothyroidism in women.

Differential effects of 3,5-T2 and T3 on the gill regeneration and metamorphosis of the Ambystoma mexicanum (axolotl).

Thyroid hormones (THs) regulate tissue remodeling processes during early- and post-embryonic stages in vertebrates. The Mexican axolotl (Ambystoma mexicanum) is a neotenic species that has lost the ability to undergo metamorphosis; however, it can be artificially induced by exogenous administration of thyroxine (T4) and 3,3',5-triiodo-L-thyronine (T3). Another TH derivative with demonstrative biological effects in fish and mammals is 3,5-diiodo-L-thyronine (3,5-T2). Because the effects of this bioactive TH remains unexplored in other vertebrates, we hypothesized that it could be biologically active in amphibians and, therefore, could induce metamorphosis in axolotl. We performed a 3,5-T2 treatment by immersion and observed that the secondary gills were retracted, similar to the onset stage phenotype; however, tissue regeneration was observed after treatment withdrawal. In contrast, T4 and T3 immersion equimolar treatments as well as a four-fold increase in 3,5-T2 concentration triggered complete metamorphosis. To identify the possible molecular mechanisms that could explain the contrasting reversible or irreversible effects of 3,5-T2 and T3 upon gill retraction, we performed a transcriptomic analysis of differential expression genes in the gills of control, 3,5-T2-treated, and T3-treated axolotls. We found that both THs modify gene expression patterns. T3 regulates 10 times more genes than 3,5-T2, suggesting that the latter has a lower affinity for TH receptors (TRs) or that these hormones could act through different TR isoforms. However, both TH treatments regulated different gene sets known to participate in tissue development and cell cycle processes. In conclusion, 3,5-T2 is a bioactive iodothyronine that promoted partial gill retraction but induced full metamorphosis in higher concentrations. Differential effects on gill retraction after 3,5,-T2 or T3 treatment could be explained by the activation of different clusters of genes related with apoptosis, regeneration, and proliferation; in addition, these effects could be initially mediated by TRs that are expressed in gills. This study showed, for the first time, the 3,5,-T2 bioactivity in a neotenic amphibian.

Role of Hormones During Gestation and Early Development: Pathways Involved in Developmental Programming.

Accumulating evidence suggests that an altered maternal milieu and environmental insults during the intrauterine and perinatal periods of life affect the developing organism, leading to detrimental long-term outcomes and often to adult pathologies through programming effects. Hormones, together with growth factors, play critical roles in the regulation of maternal-fetal and maternal-neonate interfaces, and alterations in any of them may lead to programming effects on the developing organism. In this chapter, we will review the role of sex steroids, thyroid hormones, and insulin-like growth factors, as crucial factors involved in physiological processes during pregnancy and lactation, and their role in developmental programming effects during fetal and early neonatal life. Also, we will consider epidemiological evidence and data from animal models of altered maternal hormonal environments and focus on the role of different tissues in the establishment of maternal and fetus/infant interaction. Finally, we will identify unresolved questions and discuss potential future research directions.

The Effect of Vitamin D Adequacy on Thyroid Hormones and Inflammatory Markers after Bariatric Surgery.

Vitamin D status affects the clinical and corporal outcomes of postoperative patients who undergo a Roux-en-Y gastric bypass (RYGB). The aim of this study was to evaluate the effect of adequate vitamin D serum concentrations on thyroid hormones, body weight, blood cell count, and inflammation after an RYGB. A prospective observational study was conducted with eighty-eight patients from whom we collected blood samples before and 6 months after surgery to evaluate their levels of 25-hydroxyvitamin D 25(OH)D, thyroid hormones, and their blood cell count. Their body weight, body mass index (BMI), total weight loss, and excess weight loss were also evaluated 6 and 12 months after surgery. After 6 months, 58% of the patients achieved an adequate vitamin D nutritional status. Patients in the adequate group showed a decrease in the concentration of thyroid-stimulating hormone (TSH) (3.01 vs. 2.22 µUI/mL, p = 0.017) with lower concentrations than the inadequate group at 6 months (2.22 vs. 2.84 µUI/mL, p = 0.020). Six months after surgery, the group with vitamin D adequacy showed a significantly lower BMI compared with the inadequate group at 12 months (31.51 vs. 35.04 kg/m2, p = 0.018). An adequate vitamin D nutritional status seems to favor a significant improvement in one's thyroid hormone levels, immune inflammatory profile, and weight loss performance after an RYGB.

Influence of carvedilol and thyroid hormones on inflammatory proteins and cardioprotective factor HIF-1α in the infarcted heart.

Inflammatory pathways of Toll-like receptor 4 (TLR4) and NLRP3 inflammasome contribute to acute myocardial infarction (AMI) pathophysiology. The hypoxia-inducible factor 1α (HIF-1α), however, is a key transcription factor related to cardioprotection. This study aimed to compare the influence of carvedilol and thyroid hormones (TH) on inflammatory and HIF-1α proteins and on cardiac haemodynamics in the infarcted heart. Male Wistar rats were allocated into five groups: sham-operated group (SHAM), infarcted group (MI), infarcted treated with the carvedilol group (MI + C), infarcted treated with the TH group (MI + TH), and infarcted co-treated with the carvedilol and TH group (MI + C + TH). Haemodynamic analysis was assessed 15 days post-AMI. The left ventricle (LV) was collected for morphometric and Western blot analysis. The MI group presented LV systolic pressure reduction, LV end-diastolic pressure elevation, and contractility index decrease compared to the SHAM group. The MI + C, MI + TH, and MI + C + TH groups did not reveal such alterations compared to the SHAM group. The MI + TH and MI + C + TH groups presented reduced MyD88 and NLRP3 and increased HIF-1α levels. In conclusion, all treatments preserve the cardiac haemodynamic, and only TH, as isolated treatment or in co-treatment with carvedilol, was able to reduce MyD88 and NLRP3 and increase HIF-1α in the infarcted heart.

RNA-seq reveals that anti-obesity irisin and triiodothyronine (T3) hormones differentially affect the purinergic signaling transcriptomics in differentiated human adipocytes.

The anti-obesity thyroid hormone, triiodothyronine (T3), and irisin, an exercise- and/or cold-induced myokine, stimulate thermogenesis and energy consumption while decreasing lipid accumulation. The involvement of ATP signaling in adipocyte cell function and obesity has attracted increasing attention, but the crosstalk between the purinergic signaling cascade and anti-obesity hormones lacks experimental evidence. In this study, we investigated the effects of T3 and irisin in the transcriptomics of membrane-bound purinoceptors, ectonucleotidase enzymes and nucleoside transporters participating in the purinergic signaling in cultured human adipocytes. The RNA-seq analysis revealed that differentiated adipocytes express high amounts of ADORA1, P2RY11, P2RY12, and P2RX6 gene transcripts, along with abundant levels of transcriptional products encoding to purine metabolizing enzymes (ENPP2, ENPP1, NT5E, ADA and ADK) and transporters (SLC29A1, SCL29A2). The transcriptomics of purinergic signaling markers changed in parallel to the upsurge of "browning" adipocyte markers, like UCP1 and P2RX5, after treatment with T3 and irisin. Upregulation of ADORA1, ADORA2A and P2RX4 gene transcription was obtained with irisin, whereas T3 preferentially upregulated NT5E, SLC29A2 and P2RY11 genes. Irisin was more powerful than T3 towards inhibition of the leptin gene transcription, the SCL29A1 gene encoding for the ENT1 transporter, the E-NPP2 (autotaxin) gene, and genes that encode for two ADP-sensitive P2Y receptors, P2RY1 and P2RY12. These findings indicate that anti-obesity irisin and T3 hormones differentially affect the purinergic signaling transcriptomics, which might point towards new directions for the treatment of obesity and related metabolic disorders that are worth to be pursued in future functional studies.