Dose Of TSH Research Articles

Recombinant Human TSH Fails to Induce the Proliferation and Migration of Papillary Thyroid Carcinoma Cell Lines.

Thyrotropin (TSH) suppression is required in the management of patients with papillary thyroid carcinoma (PTC) to improve their outcomes, inevitably causing iatrogenic thyrotoxicosis. Nevertheless, the evidence supporting this practice remains limited and weak, and in vitro studies examining the mitogenic effects of TSH in cancerous cells used supraphysiological doses of bovine TSH, which produced conflicting results. Our study explores, for the first time, the impact of human recombinant thyrotropin (rh-TSH) on human PTC cell lines (K1 and TPC-1) that were transformed to overexpress the thyrotropin receptor (TSHR). The cells were treated with escalating doses of rh-TSH under various conditions, such as the presence or absence of insulin. The expression levels of TSHR and thyroglobulin (Tg) were determined, and subsequently, the proliferation and migration of both transformed and non-transformed cells were assessed. Under the conditions employed, rh-TSH was not adequate to induce either the proliferation or the migration rate of the cells, while Tg expression was increased. Our experiments indicate that clinically relevant concentrations of rh-TSH cannot induce proliferation and migration in PTC cell lines, even after the overexpression of TSHR. Further research is warranted to dissect the underlying molecular mechanisms, and these results could translate into better management of treatment for PTC patients.

Evolution in the management of thyroid surgery over a period of 15 years in a Belgian center

BackgroundGuidelines for thyroid surgery have evolved to reflect advances in medical knowledge and decrease the overdiagnosis of low-risk thyroid cancer. Our goal was to analyze the change made in operative thyroid management and the impact on thyroid cancer diagnosis.BackgroundGuidelines for thyroid surgery have evolved to reflect advances in medical knowledge and decrease overdiagnosis of low risk thyroid cancer. Our goal was to study the evolution, over a long period, of pre- and postoperative management and the influence on histological cancer diagnosis and, more particularly, microcancer.MethodsIn this retrospective cohort study, we included 891 consecutive patients who underwent thyroid surgery between 2007 and 2020.ResultsRespectively 305, 290 and 266 patients underwent surgery over the 3 periods of 2007–2010, 2011–2015 and 2016–2020. In all three periods, women represented approximately 70% of the population, and the mean age was 54 years old (range: 67). Most surgeries (90%) involved total thyroidectomies. Over the study period, the proportion of preoperative fine needle aspiration (FNA) increased from 13 to 55%, p < 0,01. Cancer was found in a total of 116 patients: 35 (11%) patients between 2007 and 2010, 50 (17%) between 2011 and 2015 and 32 (12%) between 2016 and 2020 (p = 0.08). For all 3 periods, papillary thyroid cancer (PTC) was the most prevalent, at approximately 80%. The proportion of thyroid cancer > T1a increased significantly from 37% (2011–2015 period) to 81% (2016–2020 period), p = 0.001. Patients treated with radioiodine remained relatively stable (approximately 60%) but were more frequently treated with a low dose of radioiodine (p < 0.01) and recombinant human TSH (p < 0.01). Operative thyroid weight decreased over time in all but the low-risk T1a PTC cases.ConclusionsOver a period of 15 years and according to the evolution of recommendations, the care of patients who underwent thyroid surgery changed with the increased use of preoperative FNA. This change came with a decrease in low-risk T1a PTC.

Efficacy of Combined Photobiomodulation Therapy with Supplements versus Supplements alone in Restoring Thyroid Gland Homeostasis in Hashimoto Thyroiditis: A Clinical Feasibility Parallel Trial with 6-Months Follow-Up.

Hashimoto thyroiditis (HT) is a thyroid-specific autoimmune disorder, triggering hypothyroidism in a population with an adequate dietary intake. Despite the current conventional treatment focuses on the permanent replacement of levothyroxine (LT4) deficiency, it appears that thyroid autoimmunity remains the cause of persistent symptoms in patients with HT, even when they achieve to be euthyroid from a biochemical standpoint. Photobiomodulation (PBM) showed to be an effective therapy in the management of autoimmune diseases, but with limited evidence. Hence, our study was conducted to appraise the efficacy of PBM therapy with supplements in restoring thyroid gland homeostasis in patients with HT compared with supplements alone. Seventy-four female subjects aged between 20 and 50 years old were recruited and divided equally into two groups: PBM and supplements group (group 1); and supplements alone group (group 2). The PBM dosimetry and treatment protocols were as follows: wavelength, 820 nm; power output, 200 mW; continuous emission mode; irradiating time, 20 s per point; fluence, 32 J/cm2 per point; treatment frequency, twice a week (excluding weekends); and treatment duration, three consecutive weeks. Whereas, the supplements protocol for both groups was the same, as follows: subjects with a serum level of vitamin D3 <40 ng/dL, who received replacement according to their serum levels, and all the subjects had a daily intake of 100 µg of oral selenium. The biochemical (FT3, FT4, antiTPO and antiTG) and anthropometric measurements were evaluated. Our findings showed significant improvement in group 1 parameters (PBM+ supplements) compared with group 2 (supplements only) in terms of weight loss and reduction in the following parameters: BMI, hip and waist circumference, waist/hip ratio, TSH, antiTPO, antiTG and treatment dose of LT4 (p < 0.05). Our results, for the first time, demonstrated an efficacy of PBM delivered at a lower fluence with supplements in restoring thyroid function, anthropometric parameters and lifestyle factors in patients with HT. Hence, extensive studies with a longer follow-up period are warranted.

Benign thyroid nodules respond to a single administration of 0.3mg recombinant human thyrotropin with highly variable volume increase.

The nature of thyroid nodules is heterogenous. Most of them are benign and, in the absence of pressure symptoms of adjunct structures, no treatment is needed. Our objective was to investigate the acute effects of a low dose of recombinant human TSH (rhTSH) on the volume of benign thyroid nodules. we studied 27 nodules (14 isoechoic and 13 hypoechoic) in 15 (11 women and 4 men; mean age: 51.0 ± 15.9 years) consecutive patients with one to three well-separated asymptomatic benign thyroid nodules. All subjects were euthyroid, with negative thyroid antibodies, and none received levothyroxine. The total thyroid volume and thyroid nodule volume were sonographically determined by two independent examiners (P.B. and M.M.) before, 48 hours and 6 months post intramuscular (IM) administration of 0.3mg rhTSH, and the mean values of the two examiners' measurements were used; thyroid function tests were obtained at the same time points. The mean volume of isoechoic nodules increased by 57.3%, of hypoechoic nodules by 46.6% and of the surrounding thyroid parenchyma by 70.4% 48 hours post-rhTSH; mean volumes had returned to baseline levels 6 months later. A large variance in the volume change responses was observed. The relative change in nodule volume (defined as the percent change in nodule volume divided by the percent change in the surrounding parenchyma) from baseline to 48 hours was significantly higher in isoechoic versus hypoechoic nodules (p<0.05). A single dose of 0.3 mg rhTSH transiently increased the volume of benign thyroid nodules. The increase was more pronounced in isoechoic nodules and had a great variability. Our findings could be useful in the management of benign thyroid nodules, by helping in understanding which nodules would be more responsive to TSH suppression therapy.

The influence of age and body weight on levothyroxine replacement dosage to achieve euthyroidism in patients with primary hypothyroidism

IntroductionAlthough, it is generally held that the levothyroxine (LT4) dose tends to decrease with age, this theory remains controversial. Our objective was to assess whether the LT4 dose required to achieve euthyroid status varies according to age, body weight (BW), sex, menopausal status, or antibody status. Materials and methodsA cross-sectional study was performed from the retrospective review of the charts of patients with a previous diagnosis of primary hypothyroidism in treatment with LT4 and in a euthyroid state. Sex, age, actual body weight (ABW), TSH, and LT4 dose were recorded. Patients were grouped according to age ranges (18–44, 45–65, and over 65 years). A euthyroid state was defined as a serum TSH within the range of 0.4–4μIU/ml. A multiple linear regression model was performed to assess the LT4 dose and age, gender, antibody status, and ABW. ResultsA total of 882 charts of patients were reviewed. 586 patients met the inclusion criteria. The median age was 55 years. There was no correlation between the LT4 dose and age. A positive correlation was observed between the LT4 dose and ABW, but not with the ideal BW. Linear regression analysis showed that positivity antibody and ABW have a significant effect on the LT4 dose. Comparison of the LT4 dose between the different age groups showed no difference. ConclusionOur study demonstrates that the dose of LT4 necessary to achieve euthyroidism is influenced by ABW and the presence of antibodies. Age and menopause did not influence the required daily dose of LT4.

1748P Predictive role of serum thyroglobulin after surgery and radioactive iodine therapy in patients with differentiated thyroid carcinoma

Thyroidectomy followed by Radioactive Iodine Therapy (RAI) is the treatment of choice for differentiated thyroid carcinoma (DTC). The serum thyroglobulin (Tg) measurement has proved to be useful for predicting persistent and/or recurrence of disease during the follow-up of DTC patients. In our study, we evaluated the predictive value of serum Tg measured in 3 different occasions: i) in euthyroidism with TSH <5 (Tg pre-131I), 40 days after surgery before thyroid remnant ablation; ii) on the day of ablative RAI after 2 doses of Thyrogen and TSH >50 (Tg at-131I); iii) one week after ablative RAI (Tg after-131I).

The influence of age and body weight on levothyroxine replacement dosage to achieve euthyroidism in patients with primary hypothyroidism

IntroductionAlthough, it is generally held that the levothyroxine (LT4) dose tends to decrease with age, this theory remains controversial. Our objective was to assess whether the LT4 dose required to achieve euthyroid status varies according to age, body weight (BW), sex, menopausal status, or antibody status. Materials and methodsA cross-sectional study was performed from the retrospective review of the charts of patients with a previous diagnosis of primary hypothyroidism in treatment with LT4 and in a euthyroid state. Sex, age, actual body weight (ABW), TSH, and LT4 dose were recorded. Patients were grouped according to age ranges (18–44, 45–65, and over 65 years). A euthyroid state was defined as a serum TSH within the range of 0.4–4μIU/ml. A multiple linear regression model was performed to assess the LT4 dose and age, gender, antibody status, and ABW. ResultsA total of 882 charts of patients were reviewed. 586 patients met the inclusion criteria. The median age was 55 years. There was no correlation between the LT4 dose and age. A positive correlation was observed between the LT4 dose and ABW, but not with the ideal BW. Linear regression analysis showed that positivity antibody and ABW have a significant effect on the LT4 dose. Comparison of the LT4 dose between the different age groups showed no difference. ConclusionOur study demonstrates that the dose of LT4 necessary to achieve euthyroidism is influenced by ABW and the presence of antibodies. Age and menopause did not influence the required daily dose of LT4.

Thyrotropin regulation of differentiated gene transcription in adult human thyrocytes in primary culture

Thyroid transcription factors (TTFs) - NKX2-1, FOXE1, PAX8 and HHEX - regulate multiple genes involved in thyroid development in mice but little is known about TTF regulation of thyroid-specific genes - thyroglobulin (TG), thyroid peroxidase (TPO), deiodinase type 2 (DIO2), sodium/iodide symporter (NIS) and TSH receptor (TSHR) - in adult, human thyrocytes. Thyrotropin (thyroid-stimulating hormone, TSH) regulation of thyroid-specific gene expression in primary cultures of human thyrocytes is biphasic yielding an inverted U-shaped dose-response curve (IUDRC) with upregulation at low doses and decreases at high doses. Herein we show that NKX2-1, FOXE1 and PAX8 are required for TSH-induced upregulation of the mRNA levels of TG, TPO, DIO2, NIS, and TSHR whereas HHEX has little effect on the levels of these thyroid-specific gene mRNAs. We show that TSH-induced upregulation is mediated by changes in their transcription and not by changes in the degradation of their mRNAs. In contrast to the IUDRC of thyroid-specific genes, TSH effects on the levels of the mRNAs for NKX2-1, FOXE1 and PAX8 exhibit monophasic decreases at high doses of TSH whereas TSH regulation of HHEX mRNA levels exhibits an IUDRC that overlaps the IUDRC of thyroid-specific genes. In contrast to findings during mouse development, TTFs do not have major effects on the levels of other TTF mRNAs in adult, human thyrocytes. Thus, we found similarities and important differences in the regulation of thyroid-specific genes in mouse development and TSH regulation of these genes in adult, human thyrocytes.

SUN-420 Spontaneous Changes in TSH Levels After Thyroidectomy During Long-Term Follow-Up

Background. Spontaneous serum TSH variations during levothyroxine replacement therapy and multiple dose changes in athyreotic patients seem to be frequent in clinical practice. Aim. To describe the rate and extent of spontaneous serum TSH variations in patients after total thyroidectomy for differentiated thyroid cancer (DTC) in real-life practice, and the number of resulting levothyroxine (LT4) dose adjustments. Methods. Data of DTC patients were prospectively collected at a single referral center between January 2005 and May 2019. TSH and fT4 serum levels, LT4 dose and formulation, and concomitant medications were recorded at 1, 3, and 12 months after primary treatment (surgery ± radioiodine therapy), and then yearly; the data were retrospectively evaluated for this study. Visit at one month was used to tailor LT4 dose and was not considered into the data analysis. Patients with structural evidence of disease or during pregnancy were excluded. Results. Data of 2883 evaluations (472 patients) were collected; at baseline, the median age was 49.7 years, 73.5% were females. The LT4 formulation administered at baseline were tablets (84.9%), liquid solution (11.4%), or soft-gel capsule (3.7%). Overall, in 27.5% of clinical evaluation with unchanged levothyroxine dose (341/1243), there were meaningful spontaneous TSH variations (defined as delta TSH > 1.5 mcUI/ml) at yearly follow-up visit. It is clinically significant: in 6.6% of visits, overt thyrotoxicosis was recorded. Furthermore, the treating clinicians decided to change the LT4 dose in 37.1% of cases. These figures were not significantly higher in the first years, and a rate above 25% persist even after ten years of follow-up. The median maintenance dose needed was 1.61 (interquartile range [IQR] 1.41-1.92) mcg/Kg/day for tablets, 1.54 (IQR 1.39-1.79) mcg/Kg/day for liquid solution, and 1.46 (IQR 1.23-1.71) mcg/Kg/day for soft-gel capsules. After correction for daily dose, there was no difference in the rate of TSH variations > 1.5 mcUI/ml, or in the absolute value of median delta of TSH between the three formulations. In 20.1% of patients, the LT4 formulation was changed during the follow-up: it was more common in patients with a known gastroenteric disease (OR 1.76, p=0.03). Conclusions. TSH spontaneous variations and dose adjustments are very common in patients after total thyroidectomy, even during long-term follow-up: wide variations happen in more than 1/4 of all visits, and dose changes are needed in more than 1/3 of all evaluations. We were more inclined to change LT4 formulation in patients with known interference in LT4 absorption: however, no difference in TSH variations was recorded between users of three different formulations, even if soft-gel capsules seem to have a lower maintenance dose.

TSH Receptor Homodimerization in Regulation of cAMP Production in Human Thyrocytes in vitro.

Thyrotropin hormone (TSH) was reported to exhibit biphasic regulation of cAMP production in human thyroid slices; specifically, upregulation at low TSH doses transitioning to inhibition at high doses. We observed this phenomenon in HEK293 cells overexpressing TSH receptors (TSHRs) but in only 25% of human thyrocytes (hThyros) in vitro. Because TSHR expression in hThyros in vitro was low, we tested the hypothesis that high, in situ levels of TSHRs were needed for biphasic cAMP regulation. We increased expression of TSHRs by infecting hThyros with adenoviruses expressing human TSHR (AdhTSHR), measured TSH-stimulated cAMP production and TSHR homodimerization. TSHR mRNA levels in hThyros in vitro were 100-fold lower than in human thyroid tissue. AdhTSHR infection increased TSHR mRNA expression to levels found in thyroid tissue and flow cytometry showed that cell-surface TSHRs increased more than 15-fold. Most uninfected hThyro preparations exhibited monotonic cAMP production. In contrast, most hThyro preparations infected with AdhTSHR expressing TSHR at in vivo levels exhibited biphasic TSH dose responses. Treatment of AdhTSHR-infected hThyros with pertussis toxin resulted in monotonic dose response curves demonstrating that lower levels of cAMP production at high TSH doses were mediated by Gi/Go proteins. Proximity ligation assays confirmed that AdhTSHR infection markedly increased the number of TSHR homodimers. We conclude that in situ levels of TSHRs as homodimers are needed for hThyros to exhibit biphasic TSH regulation of cAMP production.

Prospective evaluation of autoimmune and non-autoimmune subclinical hypothyroidism in Down syndrome children.

To evaluate the prevalence and natural course of autoimmune and non-autoimmune subclinical hypothyroidism (SH) in Down syndrome (DS) children and adolescents. Prospective multicenter study. For the study, 101 DS patients with SH (TSH 5-10 mIU/L; FT4 12-22 pmol/L), aged 2-17 years at SH diagnosis were enrolled. Annual monitoring of TSH, FT4, BMI, height, and L-thyroxine dose was recorded for 5 years. Thyroid autoimmunity was tested at diagnosis and at the end of follow-up. Thirty-seven out of 101 patients displayed autoantibody positivity (group A); the remaining 64 were classified as non-autoimmune SH (group B). Group A was characterized by higher median age at SH diagnosis and by more frequent family history of thyroid disease (6.6 vs 4.7 years, P = 0.001; 32.4% vs 7.8%, P = 0.001 respectively), whereas congenital heart defects were more common in group B (65.6% vs 43.2%, P = 0.028). Gender, median BMI (SDS), height (SDS), FT4, and TSH were similar in both groups. At the end of follow-up: 35.1% of group A patients developed overt hypothyroidism (OH) vs 17.2% of group B (P = 0.041); 31.25% of group B vs 10.8% of group A became biochemically euthyroid (P = 0.02); and 37.8% of group A vs 51.5% of group B still had SH condition (P = 0.183). Logistic regression suggested autoimmunity (OR = 3.2) and baseline TSH values (OR = 1.13) as predictive factors of the evolution from SH to OH. In DS children, non-autoimmune SH showed higher prevalence and earlier onset. The risk of thyroid function deterioration over time seems to be influenced by thyroid autoimmunity and higher baseline TSH values.

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 β-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 β-arrestin 1 or β-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 β-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.

Multiple Transduction Pathways Mediate Thyrotropin Receptor Signaling in Preosteoblast-Like Cells.

It has been shown that the TSH receptor (TSHR) couples to a number of different signaling pathways, although the Gs-cAMP pathway has been considered primary. Here, we measured the effects of TSH on bone marker mRNA and protein expression in preosteoblast-like U2OS cells stably expressing TSHRs. We determined which signaling cascades are involved in the regulation of IL-11, osteopontin (OPN), and alkaline phosphatase (ALPL). We demonstrated that TSH-induced up-regulation of IL-11 is primarily mediated via the Gs pathway as IL-11 was up-regulated by forskolin (FSK), an adenylyl cyclase activator, and inhibited by protein kinase A inhibitor H-89 and by silencing of Gαs by small interfering RNA. OPN levels were not affected by FSK, but its up-regulation was inhibited by TSHR/Gi-uncoupling by pertussis toxin. Pertussis toxin decreased p38 MAPK kinase phosphorylation, and a p38 inhibitor and small interfering RNA knockdown of p38α inhibited OPN induction by TSH. Up-regulation of ALPL expression required high doses of TSH (EC50 = 395nM), whereas low doses (EC50 = 19nM) were inhibitory. FSK-stimulated cAMP production decreased basal ALPL expression, whereas protein kinase A inhibition by H-89 and silencing of Gαs increased basal levels of ALPL. Knockdown of Gαq/11 and a protein kinase C inhibitor decreased TSH-stimulated up-regulation of ALPL, whereas a protein kinase C activator increased ALPL levels. A MAPK inhibitor and silencing of ERK1/2 inhibited TSH-stimulated ALPL expression. We conclude that TSH regulates expression of different bone markers via distinct signaling pathways.

Thyroid function and bone mineral density among Indian subjects

Background:Thyroid hormones affect bone remodeling in patients with thyroid disease by acting directly or indirectly on bone cells. In view of limited information on correlation of thyroid function with bone mineral density (BMD) in euthyroid subjects, we undertook this study to evaluate the correlation between thyroid function with BMD in subjects with normal thyroid function and subclinical hypothyroidism.Material and Methods:A total of 1290 subjects included in this cross sectional study, were divided in Group-1 with normal thyroid function and Group-2 with subclinical hypothyroidism. Fasting blood samples were drawn for the estimation of serum 25(OH)D, intact parathyroid hormone, total and ionized calcium, inorganic phosphorus, and alkaline phosphatase. BMD at lumbar spine, femur, and forearm was measured.Results:BMD at all sites (radius, femur, and spine) were comparable in both groups. There was no difference in BMD when subjects were divided in tertiles of TSH in either group. In group-1, FT4 and TSH were positively associated with BMD at 33% radius whereas FT3 was negatively associated with BMD at femoral neck in multiple regression analysis after adjustment for age, sex, BMI, 25(OH)D and PTH levels. In group-2, there was no association observed between TSH and BMD at any site. Amongst all study subjects FT4 and FT3 were positively correlated with BMD at lumbar spine and radius respectively among all subjects.Conclusion:TSH does not affect BMD in euthyroid subjects and subjects with subclinical hypothyroidism. Thyroid hormones appear to have more pronounced positive effect on cortical than trabecular bone in euthyroid subjects.

Approach to Management of the Patient with Primary or Secondary Intrathoracic Goiter

Intrathoracic (substernal) goiter, depending on definition, is seen in up to 45% of all patients operated for goiter. It can either be primary (ectopic thyroid tissue detached from a cervical thyroid mass), which is very rare (1%), or (more commonly) secondary, where a portion of the goiter extends retrosternally. There is no consensus on diagnostic or therapeutic management, partly because many are asymptomatic. Classification involves functional characterization with serum TSH and morphological characterization with diagnostic imaging and cytology to rule out malignancy, which is not more common than in cervical goiters. Pulmonary function is often affected in asymptomatic individuals also. Therefore, but also because natural history is continuous growth and evolution from euthyroidism to hyperthyroidism, most experts recommend therapy. In primary as well as secondary intrathoracic goiter, the therapy of choice is total/near-total thyroidectomy and subsequent levothyroxine substitution. Data suggest that complications are only slightly more prevalent than in cervical goiters. Although levothyroxine is not recommended for goiter shrinkage, there is increasing focus on radioactive iodine as an alternative to surgery in secondary intrathoracic goiters. Here it can reduce thyroid size by on average 40% after 1 yr and improve respiratory function and quality of life. Recent studies show that recombinant human TSH, currently used off-label, can augment the radioiodine-related goiter shrinkage by 30-50%. With currently used doses of recombinant human TSH, the side effects, besides hypothyroidism, are rare and mild. Future studies should also explore the use of radioiodine in primary intrathoracic goiter and compare surgery and radioiodine, head to head.

Single photon emission computed tomography imaging for temporal dynamics of thyroidal and salivary radionuclide accumulation in 17-allyamino-17-demothoxygeldanamycin-treated thyroid cancer mouse model

Selective iodide uptake and prolonged iodine retention in the thyroid is the basis for targeted radioiodine therapy for thyroid cancer patients; however, salivary gland dysfunction is the most frequent nonthyroidal complications. In this study, we have used noninvasive single photon emission computed tomography functional imaging to quantify the temporal dynamics of thyroidal and salivary radioiodine accumulation in mice. At 60 min post radionuclide injection, radionuclide accumulation in the salivary gland was generally higher than that in thyroid due to much larger volume of the salivary gland. However, radionuclide accumulation per anatomic unit in the salivary gland was lower than that in thyroid and was comparable among mice of different age and gender. Differently, radionuclide accumulation per anatomic unit in thyroid varied greatly among mice. The extent of thyroidal radioiodine accumulation stimulated by a single dose of exogenous bovine TSH (bTSH) in triiodothyronine (T₃)-supplemented mice was much less than that in mice received neither bTSH nor T₃ (nontreated mice), suggesting that the duration of elevated serum TSH level is important to maximize thyroidal radioiodine accumulation. Furthermore, the extent and duration of radioiodine accumulation stimulated by bTSH was less in the thyroids of the thyroid-targeted RET/PTC1 (thyroglobulin (Tg)-PTC1) mice bearing thyroid tumors compared with the thyroids in wild-type (WT) mice. Finally, the effect of 17-allyamino-17-demothoxygeldanamycin on increasing thyroidal, but not salivary, radioiodine accumulation was validated in both WT mice and Tg-PTC1 preclinical thyroid cancer mouse model.

Die canine Hypothyreose – eine diagnostische Herausforderung?

Hypothyroidism is one of the most common endocrinopathies in dogs. Clinical symptoms and hematological and biochemical parameters lead to a first suspicion. To confirm diagnosis can be challenging, however. Determination of total serum T4 concentration is accepted as the primary screening test for the disease, and low serum T4 concentrations are intuitively suggestive of hypothyroidism. However it is well known that low T4 concentrations are frequently encountered in euthyroid dogs with various nonthyroidal diseases and in dogs receiving certain pharmacologic agents. Since assessment of endogenous TSH (canine TSH) using current canine TSH assays shows normal values in a high percentage of hypothyroid dogs (up to 40%), its diagnostic value is only limited. The TSH-stimulation test can still be recognized as the gold standard for the diagnosis of hypothyroidism in dogs. Determination of circulating T4 concentration before and 6 hours after the administration of exogenous TSH (recombinant human TSH, Thyrogen ® ) provides an assessment of the functional reserve capacity of the thyroid gland with minimal change in post-TSH T4 concentration, compared with the basal concentration, expected in dogs with hypothyroidism. Also this test can be influenced by nonthyroidal illness and by medications known to affect thyroid function. This suppressing influence seems to be less pronounced using a higher dose of TSH. Therefore, to improve the discriminatory power of the TSH stimulation test to differentiate between euthyroid-sick and primary hypothyroidism, the higher dose should be used in cases in which testing cannot be delayed. More recently, ultrasonography and scintigraphy have been used for the diagnosis of primary hypothyroidism. Using ultrasonography, a sensitivity of 98% was reported if size and echogenicity of the gland were combined. However, specificity was as low as 77% and care must be taken when measuring the gland because of a relatively high interobserver variability. Preliminary results using scintigraphy to discriminate between hypothyroid and non-thyroidal illness seem promising. However, due to its limited availability and the high expenditure, to date it cannot be used in clinical practice. Therefore, at present, if test results are obscure and a final diagnosis cannot be made, it is recommended to repeat the tests at a later time point.

Resveratrol Increases Iodide Trapping in the Rat Thyroid Cell Line FRTL-5

Resveratrol, a polyphenol found in grapes, exhibits several beneficial health effects by its antioxidant, antiinflammatory, and chemopreventive properties. The aim of the present study was to determine the effect of resveratrol on iodide trapping and efflux as well as its mode of action using FRTL-5 cells, having in mind the pivotal role of the natrium iodide symporter (NIS) in the treatment of differentiated thyroid cancers. Cells were treated with resveratrol for various times and doses, in the presence or absence of thyrotropin (TSH). Iodide trapping, iodide efflux, rat NIS (rNIS) protein expression, and cyclic AMP (cAMP) production were evaluated. Resveratrol increased iodide trapping in a time-dependent (optimal 6 hours) and dose-dependent (100 microM) way in the presence of TSH. It showed an additive effect when concomitantly added with an optimal dose of TSH. Resveratrol (50 microM) increased (threefold) rNIS protein expression. In TSH-deprived cells, resveratrol also provoked an increase in rNIS protein (>3-fold in 6 hours) with an optimum at 40 microM. Resveratrol did not inhibit iodide efflux from FRTL-5 cells. It neither increased intracellular cAMP nor induced the arborization of living cells, two TSH-induced effects. A non-cAMP mode of action is highly suspected. Resveratrol increases iodide trapping in FRTL-5 cells, increasing iodide influx and rNIS protein level even in the absence of TSH. It has an additive effect with TSH. Consequently, resveratrol could be a promising molecule for radioiodide therapy in follicular and papillary differentiated thyroid carcinoma in association with recombinant human TSH.

Graves' disease and radioiodine therapy

This study was performed to determine the results of ablative radioiodine therapy (RIT) when the achieved dose in the thyroid was above 200 Gy and to characterize predictive factors for treatment outcome. A total of 571 consecutive patients were observed for 12 months between July 2001 and June 2004. Inclusion criteria were a confirmed diagnosis Graves' disease, compensation of hyperthyroidism and withdrawal of antithyroid drugs two days before preliminary radioiodine-testing and RIT. The intended dose was 250 Gy and the therapeutically achieved dose was calculated from serial uptake measurements. The end-point measure was thyroid function 12 months after RIT; success was defined as elimination of hyperthyroidism. The relation between success rate and the achieved dose, thyroid volume, age and sex of patients, TSH- and TRAb-values and presence of ophthalmopathy was analysed. Relief from hyperthyroidism was achieved in 96% of patients who received more than 200 Gy, even for thyroid volumes >40 ml. The success of ablative RIT was not influenced by age or sex of patients, or by TSH- or TRAb values or concomitant ophthalmopathy. The mean achieved dose in the thyroid was 298 Gy with a standard deviation of 74.6 Gy. To achieve a dose of over 200 Gy with the above standard deviation, we recommend calculating an intended dose of 250 Gy and using a dosimetric approach with early and late uptake values in the radioiodine test, to allow early therapeutic intervention should the posttherapeutic thyroid dose fall unexpectedly below 200 Gy.

Effect of phosphate binders upon TSH and l-thyroxine dose in patients on thyroid replacement

While calcium carbonate is known to interfere with the gastrointestinal absorption of levothyroxine, we hypothesized that other phosphate binders would also bind to levothyroxine and decrease bioavailability of levothyroxine in dialysis patients. The records of 1,566 patients on hemodialysis who were being treated by the Hypertension, Nephrology, Dialysis, and Transplantation Center (the regional renal referral center for Eastern Alabama, USA) were evaluated. The type of phosphate binder and amount were then correlated (two-tailed Pearson Correlation) to TSH levels, serum phosphorus and the amount of levothyroxine taken. Friedman Test and Wilcoxon Signed Ranks Test were performed to analyze the significance of difference in thyroxine dosing and TSH levels between the different phosphate binders. Sixty-seven patients were identified who were taking levothyroxine while taking three different kinds of phosphate binders; namely, calcium carbonate, calcium acetate, and sevelamer HCl. We found that the TSH levels of patients on calcium carbonate (P = 0.002) and sevelamer HCl (P = 0.033) were significantly higher than patients on calcium acetate with the difference increasing with time on each binder. Sevelamer was also found to be associated with significantly higher dosing requirement of thyroid replacement than those on either calcium carbonate or calcium acetate (Z = -3.17, P = 0.001). Sevelamer (but not calcium acetate) in addition to calcium carbonate appears to interfere with the bioavailability of levothyroxine.