Thyroid-Stimulating Hormone Inhibits Insulin Receptor Substrate-1 Expression and Tyrosyl Phosphorylation in 3T3-L1 Adipocytes by Increasing NF-κB DNA-Binding Activity.

Background: Abundant evidence indicates that thyroid-stimulating hormone (TSH) levels are associated with insulin resistance in adipocytes. However, the potential mechanism of the association remains uncertain. The objective of this study was to determine the potential role of TSH in the suppression of insulin receptor substrate-1 (IRS-1) expression and IRS-1 tyrosyl phosphorylation, which might contribute to insulin resistance. Methods: Mouse 3T3-L1 preadipocytes were differentiated into adipocytes. After treatment with 0.01, 0.1, and 1.0 mIU/ml bovine TSH, the TNF-α concentration in the medium was determined by enzyme-linked immunosorbent assay (ELISA). Nuclear factor-kappa B (NF-κB) DNA-binding activity was quantified by electrophoretic mobility shift assay (EMSA). IRS-1 levels in adipocytes were quantified by Western blotting, and tyrosine phosphorylation was measured by immunoprecipitation. Results: TSH induced TNF-α secretion in a dose-dependent manner. There was a significant positive correlation between NF-κB DNA-binding activity and TNF-α secretion. This effect and correlation were weakened by BAY 11-7082 (a nuclear NF-κB inhibitor) and H89 (an inhibitor of cyclic adenosine monophosphate- (cAMP-) dependent protein kinase A (PKA)). Treatment of cultured adipocytes with TSH inhibited insulin-stimulated IRS-1 tyrosyl phosphorylation but promoted TSH-dependent secretion of TNF-α and activation of NF-κB DNA-binding activity. The effects of TSH were significantly inhibited by BAY 11-7082 and H89 and were completely blocked by the TNF-α antagonist WP9QY. Conclusion: TSH inhibited IRS-1 protein expression and tyrosyl phosphorylation in 3T3-L1 adipocytes by stimulating TNF-α production via promotion of NF-κB DNA-binding activity. TSH might play a pivotal role in the development of insulin resistance.

A practical individualized radiation precaution based on the dose rate at release time after inpatient 131I ablation therapy.

INTRODUCTION: Retained radioactivity of 131I after ablation therapy largely differs in each patient according to factors including the amount of remnant thyroid tissue, renal function, and use of recombinant human thyroid-stimulating hormone. To reduce unnecessary restriction of patient's daily life after inpatient 131I ablation therapy, we propose a practical individualized method for radiation precaution based on dose rate at release time. METHODS: We evaluated 215 patients with differentiated thyroid cancer who underwent inpatient 131I ablation therapy following total thyroidectomy. Effective dose equivalent rates at 1-m distance were measured upon release (EDRR) on day 2 and during delayed whole-body scan (EDRD) visits on day 6‒8 after 131I administration. The biexponential model was designed to estimate total effective dose equivalent to others. To assess conservativeness of our model, EDRD estimated by our model was compared with measured EDRD. EDRR-based periods of precaution not to receiving 1 mSv of radiation exposure were estimated and compared with those based on administered radioactivities on American Thyroid Association (ATA) recommendations. RESULTS: The EDRR ranged from 1.0-48.9 µSv/hr. The measured EDRD were equal to or lower than estimated EDRD in all patients, except for one, indicating that our model is sufficiently conservative. According to our model, no subjects needed additional daytime restriction after release. The maximum permissible times for public transportation use were longer in all patients compared with those based on administered radioactivities. Nighttime restriction periods were significantly shorter than those based on administered radioactivity; median periods requiring sleeping apart were 0 (range, 0‒5), 4 (range, 1‒14), and 3 (range, 2‒13) days after release in patients treated with radioactivity doses of 2.96, 5.50, and 7.40 GBq, respectively, needing 8, 16, and 19 additional days, respectively, based on administered radioactivity. CONCLUSIONS: Radiation safety instructions using proposed method based on EDRR of individual patient could safely reduce the burden of radiation precaution.

A pre-ablative thyroid-stimulating hormone with 30-70 mIU/L achieves better response to initial radioiodine remnant ablation in differentiated thyroid carcinoma patients.

Our aim was to clarify the optimum pre-ablative thyroid-stimulating hormone (TSH) level for initial radioiodine remnant ablation (RRA) in patients with differentiated thyroid carcinoma (DTC). From December 2015 to May 2019, 689 patients undergone RRA at Nuclear Medicine Department, Second Hospital of Shandong University were included in the study. Patients were categorized by their pre-ablative TSH level grouping of < 30, 30-70 and ≥ 70 mIU/L. Response to RRA were evaluated as complete response (including excellent and indeterminate response) and incomplete response (including biochemical and structural incomplete response) after a follow-up of 6-8 months. Multivariable binary logistic regression model was used to explore the optimum pre-ablative TSH level range and independent factors associated with response to RRA. Rates of complete response to RRA were 63.04%, 74.59% and 66.41% in TSH level groups of < 30, 30-70 and ≥ 70 mIU/L, separately. With multivariate analysis, the study found that pre-ablative TSH levels, gender and lymph node dissection were independent predictors of response to RRA. TSH between 30 and 70 mIU/L had a higher rate of complete response compared with TSH < 30 mIU/L, OR 0.451 (95% CI 0.215-0.958, P = 0.036). A pre-ablative TSH level of 30-70 mIU/L was appropriate for patients with DTC to achieve a better response to RRA.

Postoperative thyroid hormone supplementation rates following thyroid lobectomy.

BACKGROUND: Thyroid lobectomy is performed for symptomatic benign nodules, indeterminate nodules, or low-risk well differentiated thyroid cancer. We aimed to determine factors associated with thyroid stimulating hormone over goal (TH) following lobectomy. METHODS: We performed a retrospective single-institution cohort study of patients undergoing thyroid lobectomy from January 2016 to December 2017. TH was defined as need for thyroid hormone in accordance with guidelines. Univariate and multivariate logistic regression analysis was performed. RESULTS: One hundred patients were included and 47% developed. TH: 73% of those with cancer, 38% with benign pathology (p = 0.002). Patients with TH were more likely to have thyroiditis 26% versus 3.8% (p = 0.002); higher preoperative TSH: mean 1.88mIU/L (SD 1.17) versus 1.16mIU/L (SD 0.77) (p = 0.0002), and smaller remnant thyroid lobe adjusted for body surface area 2.99ml/m2 versus 3.72ml/m2 (p = 0.003). CONCLUSIONS: After thyroid lobectomy, TH is associated with preoperative TSH level, thyroiditis, remnant thyroid volume, and malignancy. The majority of patients with final pathology of carcinoma will require thyroid hormone supplementation to achieve TSH goal.

Recombinant Human Thyroid-Stimulating Hormone Increases the Percentages of Natural Killer T Cells and B Lymphocytes in Human Peripheral Blood In Vivo.

Multiple cellular and humoral components of the immune system play a significant role in the physiology and pathophysiology of various organs including the thyroid. On the other hand, both thyroid hormones and thyroid-stimulating hormone (TSH) have been shown to exert immunoregulatory activities, which are difficult to assess independently in vivo. In our study we employed a unique clinical model for the assessment of TSH biological function in humans. The structure of peripheral blood mononuclear cell populations was investigated, using flow cytometry, in athyroid patients (n = 109) after treatment because of the differentiated thyroid carcinoma (DTC) at two time-points: directly before and five days after recombinant human TSH (rhTSH) administration. The analysis revealed significant increase in the percentage of natural killer T cells and B lymphocytes in the peripheral blood of rhTSH treated patients, whereas, we did not observe any effects on investigated subpopulations of dendritic cells and monocytes, T cells and natural killer cells. The findings of the study indicate the immune regulatory role of TSH, directed specifically on selected cell subtypes.

Factores clínicos y bioquímicos asociados con la tirotropina en embarazadas aparentemente sanas / Clinical and biochemical factors associated with thyrotropin in seemingly healthy pregnant women

Introducción: Los valores de tirotropina (TSH) pueden modificarse marcadamente durante el embarazo, en relación con diversos factores clínicos y bioquímicos. Objetivo: Identificar los factores clínicos y bioquímicos asociados con la tirotropina en embarazadas aparentemente sanas. Métodos: Estudio descriptivo, transversal, con 247 gestantes aparentemente sanas del municipio Plaza de la Revolución., en el periodo comprendido de septiembre de 2015 a enero de 2019. Variables analizadas: edad materna y gestacional, trimestre del embarazo, color de la piel, paridad, hábito de fumar, antecedentes familiares de enfermedad tiroidea (APF), consumo de suplementos con yodo, índice de masa corporal (IMC), presencia de bocio al examen físico, TSH, tiroxina total (T4t) y libre (T4l), triyodotironina total (T3t) y libre (T3l), gonadotropina coriónica (hCG), anticuerpos contra la peroxidasa tiroidea (AcTPO) y la tiroglobulina (AcTg) y yoduria. Resultados: La TSH (1,66 ± 0,91mUI/L) tuvo una asociación negativa con la edad materna (r = -0,17; p = 0,008), la paridad (nulíparas 1,80 ± 0,90 mUI/L, multíparas 1,45 ± 0,89 mUI/L; p = 0,003), los APF (positivos 1,56 ± 0,91 mUI/L, negativos 1,81 ± 0,89 mUI/L; p = 0,03), la T4t (r = -0,15; p = 0,02), la T4l (r = -0,23; p = 0,000) y la hCG (r = -0,52; p = 0,001). Mostraron una relación directa la edad gestacional (r = 0,25; p = 0,000) y el uso de suplementos yodados (consumo 1,96 ± 0,72mUI/L, no consumo 1,62 ± 0,93 mUI/L; p = 0,03). Conclusiones: La tirotropina presenta una relación inversa con la edad materna, la paridad, los antecedentes familiares de enfermedad tiroidea, la T4 total y libre, y la gonadotropina coriónica, y una relación directa con la edad gestacional y el consumo de suplementos con yodo(AU)

Introduction: Thyrotropin (TSH) values can be sharply modified during pregnancy, in relation to various clinical and biochemical factors. Objective: Identify clinical and biochemical factors associated with thyrotropin in seemingly healthy pregnant women. Methods: Descriptive, cross-sectional study with 247 seemingly healthy pregnant women from Plaza de la Revolution municipality in the period from September 2015 to January 2019. Variables analyzed: maternal and gestational age, trimester of pregnancy, skin color, pregnancies, smoking habit, family history of thyroid disease (APF), consumption of iodine supplements, body mass index (BMI), presence of goiter to physical examination, TSH, total and free (T4l) thyroxine (T4t), total (T3t) and free (T3l) triiodothyronine, chorionic gonadotropin (hCG), antibodies against thyroid peroxidase (AcTPO) and thyroglobulin (AcTg) and urinary iodine. Results: TSH (1.66 ± 0.91mUI/L) had a negative association with maternal age (r = -0.17; p x 0.008), pregnancy (nulliparas 1.80 ± 0.90 mUI/L, 1.45 ± 0.89 mUI/L; p x 0.003), APF (positive 1.56 ± 0.91 mUI/L, negative 1.81 ± 0.89 mUI/L; p x 0.03), the T4t (r = -0.15; p s 0.02), the T4l (r = -0.23; p x 0.000) and the hCG (r = -0.52; p x 0.001). They showed a direct relationship with gestational age (r x 0.25; p x 0.000) and the use of iodine supplements (consumption 1.96 ± 0.72mUI/L, not consumption 1.62 ± 0.93 mUI/L; p x 0.03). Conclusions: Thyrotropin has an inverse relationship with maternal age, pregnancies, family history of thyroid disease, total and free T4, and chorionic gonadotropin, and a direct relationship with gestational age and consumption of iodine supplements(AU)

Recombinant Human Thyrotropin-Stimulated Radioiodine Therapy in Patients with Multinodular Goiters: A Meta-Analysis of Randomized Controlled Trials.

A potential reduction of goiter volume (GV) of recombinant human thyrotropin (rhTSH) on multinodular goiters (MNG) was previously reported but controversial. Hence we conducted a meta-analysis to estimate the effect of rhTSH-stimulated radioiodine therapy in patients with MNG. PubMed, Cochrane, CNKI, VIP, and Wanfang databases were searched. Mean difference (MD) and odds ratios with 95% confidence intervals (95% CI) were derived by using an inverse variance random-effects model and fixed-effects model, respectively. Six studies (n=237) were involved in the analysis. For 12 months follow up, high dose (>0.1 mg) of rhTSH significantly reduced GV (MD=17.61; 95% CI=12.17 to 23.04; p<0.00001) compared with placebo. No effective pooled results of low dose of rhTSH (<0.1 mg) were applicable for only one study included. For 6 months follow up, the source of heterogeneity was determined by subgroup and sensitivity analysis. High dose group showed vast improvement in GV reduction (MD=16.62; 95% CI=1.34 to 31.90; p=0.03). The reduction of low dose group compared with placebo was inferior to high dose group. No available data were obtained to assess the influence of rhTSH after 36 months follow up for the only included study. Hypothyroidism incidence was higher for rhTSH group. No publication bias was seen. High dose of rhTSH treatment-stimulated radioactive 131I therapy after 6 months and 12 months follow up had a better effect in reducing GV, but with higher incidence of hypothyroidism. Owing to the limited methodological quality, more clinical researches are warranted in the future.

Thyroid function testing and management during and after pregnancy among women without thyroid disease before pregnancy.

BACKGROUND: Screening in pregnancy for subclinical hypothyroidism, often defined as thyroid-stimulating hormone (TSH) greater than 2.5 mIU/L or greater than 4.0 mIU/L, is controversial. We determined the frequency and distribution of TSH testing by gestational age, as well as TSH values associated with treatment during pregnancy and the frequency of postpartum continuation of thyroid hormone therapy. METHODS: We performed a retrospective cohort study of pregnancies in Alberta, Canada. We included women without thyroid disease who delivered between October 2014 and September 2017. We used delivery records, physician billings, and pharmacy and laboratory administrative data. Our key outcomes were characteristics of TSH testing and the initiation and continuation of thyroid hormone therapy. We calculated the proportion of pregnancies with thyroid testing and the frequency of each specific thyroid test. RESULTS: Of the 188 490 pregnancies included, 111 522 (59.2%) had at least 1 TSH measurement. The most common time for testing was at gestational week 5 to 6. Thyroid hormone therapy was initiated at a median gestational age of 7 (interquartile range 5-12) weeks. Among women with first TSH measurements of 4.01 to 9.99 mIU/L who were not immediately treated, the repeat TSH measurement was 4.00 mIU/L or below in 67.9% of pregnancies. Thyroid hormone was continued post partum for 44.6% of the women who started therapy during their pregnancy. INTERPRETATION: The findings of our study suggest that current practice patterns may contribute to overdiagnosis of hypothyroidism and overtreatment during pregnancy and post partum.

Thyrotropin Causes Dose-dependent Biphasic Regulation of cAMP Production Mediated by Gs and Gi/o Proteins.

The thyrotropin (TSH) receptor (TSHR) signals via G proteins of all four classes and ß-arrestin 1. Stimulation of TSHR leads to increasing cAMP production that has been reported as a monotonic dose-response curve that plateaus at high TSH doses. In HEK 293 cells overexpressing TSHRs (HEK-TSHR cells), we found that TSHR activation exhibits an "inverted U-shaped dose-response curve" with increasing cAMP production at low doses of TSH and decreased cAMP production at high doses (>1 mU/ml). Since protein kinase A inhibition by H-89 and knockdown of ß-arrestin 1 or ß-arrestin 2 did not affect the decreased cAMP production at high TSH doses, we studied the roles of TSHR downregulation and of Gi/Go proteins. A high TSH dose (100 mU/ml) caused a 33% decrease in cell-surface TSHR. However, because inhibiting TSHR downregulation with combined expression of a dominant negative dynamin 1 and ß-arrestin 2 knockdown had no effect, we concluded that downregulation is not involved in the biphasic cAMP response. Pertussis toxin, which inhibits activation of Gi/Go, abolished the biphasic response with no statistically significant difference in cAMP levels at 1 and 100 mU/ml TSH. Concordantly, co-knockdown of Gi/Go proteins increased cAMP levels stimulated by 100 mU/ml TSH from 55% to 73% of the peak level. These data show that biphasic regulation of cAMP production is mediated by Gs and Gi/Go at low and high TSH doses, respectively, which may represent a mechanism to prevent overstimulation in TSHR-expressing cells. SIGNIFICANCE STATEMENT: We demonstrate biphasic regulation of TSH-mediated cAMP production involving coupling of the TSH receptor (TSHR) to Gs at low TSH doses and to Gi/o at high TSH doses. We suggest that this biphasic cAMP response allows the TSHR to mediate responses at lower levels of TSH and that decreased cAMP production at high doses may represent a mechanism to prevent overstimulation of TSHR-expressing cells. This mechanism could prevent chronic stimulation of thyroid gland function.

Evaluation of SNA001, a Novel Recombinant Human Thyroid Stimulating Hormone Injection, in Patients With Differentiated Thyroid Carcinoma.

SNA001 is a novel recombinant human thyroid stimulating hormone (rhTSH). rhTSH has long been approved in several countries to facilitate monitoring and ablation of thyroid carcinoma without hypothyroidism caused by thyroid hormone withdrawal (THW). To assess the safety, tolerance, pharmacokinetic and pharmacodynamic properties of SNA001, the two-period (SNA001 period and THW period), dose-ascending study in well-differentiated thyroid cancer (DTC) patients was designed. Three doses (0.45 mg, 0.9 mg, and 1.35 mg) of SNA001 were intramuscularly injected, twice in the SNA001 period to stimulate iodine-131 uptake and thyroglobulin (Tg) release. 24 h after the last dose of SNA001, iodine-131 (111-185 MBq) was administrated, followed by whole-body scan (WBS) 48 h later. THW period began just after SNA001 washout and lasted for about 3-6 weeks. When TSH level was above 30 mU/L, iodine-131 (111-185 MBq) was administrated, followed by a WBS and Tg detection 48 h later. Twenty-four DTC patients after thyroidectomy were enrolled; mean peak concentrations of SNA001 in 0.45, 0.9, and 1.35 mg groups were 18.5, 26.7, and 37.0 ng/ml (about 244.7, 354.2, and 489.6 mU/L) respectively, within 28-32 h after first dose of SNA001. SNA001 was metabolized in a dose-dependent manner. The results of WBS and Tg release in the SNA001 period were compared with those in the THW period. Compared to Tg level in baseline, the Tg levels in SNA001 and THW periods were increased, with 78% of subjects showing higher Tg levels in the THW period. 100% of the patients had concordant qualitative results of the scans within two periods in three groups. Symptoms of hypothyroidism were relieved in the SNA001 period compared with THW period, though there was no significant difference in most of the scale scores. There were no serious adverse events related to SNA001; the most common adverse events were gastrointestinal symptoms of mild and transient nature. Thus, SNA001 promises to be a safe and effective method to stimulate iodine-131 uptake and Tg secretion during monitoring and ablation for DTC without the disadvantages of incidental hypothyroidism.