Increased Serum TSH Concentrations Research Articles

Possible added value of thyroglobulin antibody (TgAb) testing in the evaluation of thyroidal status of subjects with overweight or obesity

PurposeAn increase in serum TSH concentrations in the absence of thyroid disease, named isolated hyperthyrotropinemia, is frequently observed in subjects with obesity. It is directly associated with body mass index, and it is reversible following weight loss. Autoimmune hypothyroidism is frequently associated with obesity, it is usually progressive and needs replacement treatment with L-thyroxine. The aim of this study was to investigate the role of thyroglobulin antibodies (TgAb) to define the thyroidal status in subjects with overweight or obesity.MethodsThis is a retrospective study including 749 consecutive adult patients with overweight or obesity. Of those, 76 were excluded from the analysis due to hyperthyroidism, previous thyroidectomy or radioiodine therapy for hyperthyroidism, hemiagenesis or drug-induced hypothyroidism. Serum thyrotropin (TSH), free thyroxine (FT4), free 3,5,3’-triiodothyronine (FT3), TgAb and thyroperoxidase antibodies (TPOAb) were measured in all patients.ResultsOut of 673 patients, 408 did not have thyroid disease. Among patients with thyroid disease (n = 265), 130 had nodular disease with no humoral signs of thyroid autoimmunity and 135 (20%) had autoimmune thyroiditis, defined by the presence of TPOAb and/or TgAb. The prevalence of hyperthyrotropinemia, either directly measured or presumed based on L-thyroxine treatment at the time of data collection, was 63.9% in patients with both TgAb and TPOAb, 47.1% in those with isolated positivity of TPOAb, 42.8% in patients with isolated positivity of TgAb, and 14.5% in those with no detectable TgAb or TPOAb.ConclusionsOur results confirm a high prevalence of autoimmune thyroiditis (20%) in patients with obesity. TgAb may be associated with hypothyroidism in the absence of TPOAb. TgAb measurement may turn helpful to unravel a proportion of subjects that may have or may develop primary hypothyroidism requiring specific substitutive treatment.

Histological pattern and gene expression profiling of thyroid tissue in subjects with obesity.

Subjects with obesity may exhibit an increase in serum TSH concentrations. Several mechanisms have been proposed to explain this association, including the presence of a compensatory mechanism to counterbalance an accelerated turnover of thyroid hormones in subjects with obesity. This study aimed at evaluating whether the thyroids of subjects with obesity differs from those of normal-weight individuals regarding histology and gene expression profiling. Ninety-eight patients were selected among those scheduled for thyroidectomy. At histology, thyroid tissue samples were investigated for the presence of adipocytes and/or lymphocyte infiltration. In a subset of patients, the expression at mRNA level of several genes involved in metabolic pathways and immune cell-related mechanisms was quantified by NanoString Technology. The presence of adipose cells was documented in thyroid specimens from 40% normal weight, 52.9% overweight and 73.5% patients with obesity. The number of infiltrating adipocytes was greater in specimens of patients with overweight or obesity compared to normal weight. The lymphocytes common antigen (CD45) and mast cell (MC) scores, and the number of CD3+ and CD8+ lymphocytes were higher in patients with overweight and obesity than in normal-weight subjects. Several genes involved in metabolic pathways were differently expressed in patients with overweight or obesity compared to normal weight, with upregulation of Leptin receptor and downregulation of Fatty Acid-Binding Protein 5. Increased BMI is associated with adipocyte and lymphocyte infiltration of the thyroid, not related to an autoimmune process, which might affect thyroid function in subjects with obesity. A differential gene expression profiling of metabolic and immune pathways in thyroid tissues of patients with obesity was also observed.

Evaluación clínica de la técnica operatoria de la tiroidectomía total en ratas Wistar

The total thyroidectomy operative technique can be fatal in murine models, and factors such as prolonged operative time, hemorrhages and iatrogenic injuries to the recurrent laryngeal nerve are commonly associated with significant trans and postoperative mortality. In order to reduce losses and, consequently, the number of animals being tested, the present study sought to establish clinical parameters for the surgical induction of hypothyroidism in rodents. Ten Wistar rats (Rattus norvegicus) were used, randomly distributed in two groups: Control (CG, n = 5), without surgical procedure and Hypothyroidism (HTG, n = 5), rats submitted to total thyroidectomy. At the beginning of the experimental period and at 60 days, blood samples were taken to determine serum concentrations of total T3, free T4, TSH and total calcium. The mean operative time, postoperative pain signs and rectal temperature were evaluated. The operative technique proved to be safe, without the occurrence of deaths. No pain symptoms were observed in the animals during the postoperative period. Likewise, there was no occurrence of iatrogenic hypoparathyroidism, attested by the normocalcemia of animals operated on at 60 days. The average initial operative time was reduced from 75.0 ± 1.57 to 33.3 ± 6.04 minutes. All thyroidectomized animals developed hypothyroidism, characterized by a statistically significant increase in serum TSH concentrations and a reduction in the concentrations of total T3 and free T4 (P < 0.05). It was concluded that total thyroidectomy in Wistar rats is a safe, reproducible and low-cost method. It is reiterated, however, the necessary surgical training in order to reduce losses and, consequently, the number of animals being tested.

An Extremely Low Frequency Magnetic Field and Global Cerebral Ischemia Affect Pituitary ACTH and TSH Cells in Gerbils.

The neuroendocrine system can be modulated by a magnetic field and cerebral ischemia as external and internal stressors, respectively. This study deals with the separate or combined effects of an extremely low frequency (ELF) magnetic field (50 Hz, average magnetic field of 0.5 mT) for 7 days and global cerebral ischemia for 10 min on the morpho-functional features of pituitary adrenocorticotrophic (ACTH) and thyrotrophic (TSH) cells in 3-month-old gerbils. To determine the immediate and delayed effects of the applied stressors, measurements were made on the 7th and 14th days after the onset of the experiment. The ELF magnetic field and 10-min global cerebral ischemia, separately and particularly in combination, decreased (P < 0.05) the volume density of ACTH cells, while only in combination were intracellular ACTH content and plasma ACTH concentration increased (P < 0.05) on day 7. The ELF magnetic field elevated serum TSH concentration on day 7 and intracellular TSHβ content on day 14 (P < 0.05). Also, 10-min global cerebral ischemia alone increased serum TSH concentration (P < 0.05), while in combination with the ELF magnetic field it elevated (P < 0.05) intracellular TSHβ content on day 14. In conclusion, an ELF magnetic field and/or 10-min global cerebral ischemia can induce immediate and delayed stimulation of ACTH and TSH synthesis and secretion. Bioelectromagnetics. 2020;41:91-103. © 2019 Bioelectromagnetics Society.

Aging Is Associated with Low Thyroid State and Organ-Specific Sensitivity to Thyroxine

Background: Serum thyroid state in older adults correlates with extended longevity. We hypothesized that age impacts not only systemic but also organ-specific thyroid state and response to thyroxine (T4). Methods: Young (3 months) and old (23 months) male mice were analyzed at baseline and after acute T4 challenge. Age effects on circulating thyrotropin (TSH) and thyroid hormone (TH) concentrations, transcript expression in the pituitary and thyroid were compared with organ-specific responses characterized by hepatic and cardiac content of TH and TH metabolites and expression of TH-target genes, as well as hepatic deiodinase 1 activity. Results: Circulating TH concentrations and hepatic and cardiac TH content were lower in old versus young mice. After injection with T4, conversion of T4 to triiodothyronine was decreased in old mice while TH transport in liver and heart was not affected. Organ-specific TH response was augmented in old mice in liver but not heart, indicating age- and tissue-specific sensitivity to TH. A compensatory increase of thyroid stimulating hormone subunit beta expression in the pituitary and increased serum TSH concentrations, but reduced expression of thyroid differentiation markers were found in old mice. Conclusions: We suggest that a reduced activity of the aged thyroid is responsible for the systemic low TH state in old mice. Further, divergent TH metabolism and tissue response in liver and heart occur after T4 treatment in an aged organism. These rodent data are in agreement with a much narrower window for T4 substitution in the older adults to avoid overtreatment.

Influence of Stem Cell Therapy on Thyroid Function and Reactive Oxygen Species Production in Diabetic Rats.

Cell therapy with mesenchymal stem cells (MSC) has been proposed for the treatment of diabetes mellitus (DM). It is known that the prevalence of thyroid disease is higher among diabetic patients than in general population. Therefore, our aim was to investigate the effect of the treatment with MSC on thyroid function and ROS generation in an experimental model of type 1 DM. Adult male Wistar rats were divided into the following groups: control, DM (80 mg/kg BW streptozotocin, iv.) and DM+MSC. MSC treatment occurred 4 weeks after DM induction and the animals were euthanized 4 weeks after MSC administration. We also evaluated the effect of co-culture with MSC or extracellular vesicles (EV) obtained from these cells on the rat thyroid cell line PCCL3 exposed to high glucose. Thyroid H2O2 generation was increased in DM, which was reversed by MSC treatment. These changes paralled a significant DuOx1 mRNA increase. The incubation of PCCL3 with high glucose increased extracellular H2O2 generation, which was reversed by both the co-culture with MSC and EV. Even though MSC treatment normalized thyroid ROS generation, serum thyroid hormone (TH) concentration remained low, along with increased serum TSH concentrations. Thyroperoxidase (TPO) activity, was reduced in DM, and MSC treatment did not normalize TPO. Therefore, we conclude that the treatment with MSC was able to reverse the increased thyroid H2O2 generation in diabetic animals and in PCCL3 cells exposed to high glucose, an effect probably mediated by EV produced by these cells, acting in a paracrine fashion.

Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS)

Objective The aim of this study was to determine the extent of drug interactions affecting levothyroxine, using study drugs often co-administered to patients on long-term levothyroxine therapy. Design A retrospective population analysis linking biochemistry and prescription data between 1 January 1993 and 31 December 2012 was used. Patients The study population was Tayside residents prescribed levothyroxine on at least three occasions, within a six-month period, prior to the start of a study drug. Individuals acted as their own controls pre- and postinitiation of study drug. Overall, 10 999 patients (mean age 58 years, 82% female) being treated with thyroxine were included in the study. Measurements Changes in TSH following initiation of study drug. Results Iron, calcium, proton pump inhibitors and oestrogen all increased serum TSH concentration: an increase of 0·22 mU/l (P < 0.001), 0·27 mU/l (P < 0·001), 0·12 mU/l (P < 0·01), and 0·08 mU/l (P < 0·007), respectively. For these four study drugs, there was a clinically significant increase of over 5 mU/l in serum TSH, in 7·5%, 4·4%, 5·6% and 4·3% patients, respectively. There was a decrease of 0·17 mU/l (P-value 0.01) in the TSH concentration for those patients on statins. The TSH decreased by 5 mU/l in 3·7% of patients. There was no effect with H2 receptor antagonists or glucocorticoids. Conclusion This large population-based study demonstrates significant interaction between levothyroxine and iron, calcium, proton pump inhibitors, statins and oestrogens. These drugs may reduce the effectiveness of levothyroxine, and patients' TSH concentrations should be carefully monitored.

The Change of Thyroid Stimulating Hormone Values of Healthy Subjects According toTemperature and Aging

Objective: We conducted a study to investigate the normal range for TSH and within-individual variations of TSH according to temperat䴸re and aging. Patients and Methods: We enrolled patients who underwent periodic medical examinations five times over a six year period (2007.8~2013.6). Anthropometric data and thyroid ultrasonography were evaluated, and serum TSH, T3, and T4 were assayed. Results: Subjects were 19-64 years old, 120 were female, and 208 were male. Reference ranges for TSH were 0.53-4.94 mlU/L in the first test, 0.49-5.61 mlU/L in the second test, 0.46-6.06 mlU/L in the third test, 0.48-5.99 mlU/L in the fourth test, and 0.52-6.3 mlU/L in the fifth test. When the TSH level was analyzed according to temperature and sex, mean TSH was higher in months in which the average monthly temperatures were below 100C in Jinju, Gyeongnam and female. The aging and low temperatures are associated with increased serum TSH concentrations in the within-individual. Conclusions: This study showed that aging is associated with increased serum TSH concentrations in the within- individual and serum TSH concentrations are different in the within-individual according to the temperature.

Drugs that interact with levothyroxine: an observational study from the Thyroid Epidemiology, Audit and Research Study (TEARS).

The aim of this study was to determine the extent of drug interactions affecting levothyroxine, using study drugs often co-administered to patients on long-term levothyroxine therapy. A retrospective population analysis linking biochemistry and prescription data between 1 January 1993 and 31 December 2012 was used. The study population was Tayside residents prescribed levothyroxine on at least three occasions, within a six-month period, prior to the start of a study drug. Individuals acted as their own controls pre- and postinitiation of study drug. Overall, 10 999 patients (mean age 58 years, 82% female) being treated with thyroxine were included in the study. Changes in TSH following initiation of study drug. Iron, calcium, proton pump inhibitors and oestrogen all increased serum TSH concentration: an increase of 0·22 mU/l (P < 0.001), 0·27 mU/l (P < 0·001), 0·12 mU/l (P < 0·01), and 0·08 mU/l (P < 0·007), respectively. For these four study drugs, there was a clinically significant increase of over 5 mU/l in serum TSH, in 7·5%, 4·4%, 5·6% and 4·3% patients, respectively. There was a decrease of 0·17 mU/l (P-value 0.01) in the TSH concentration for those patients on statins. The TSH decreased by 5 mU/l in 3·7% of patients. There was no effect with H2 receptor antagonists or glucocorticoids. This large population-based study demonstrates significant interaction between levothyroxine and iron, calcium, proton pump inhibitors, statins and oestrogens. These drugs may reduce the effectiveness of levothyroxine, and patients' TSH concentrations should be carefully monitored.

Thyroid Hormone Profile in Rwandan Students

Aim: To illustrate the thyroid hormone profile in young adult students at moderate altitude in Rwanda. Study Design:A population-based cross-sectional study. Place and Duration of Study:The study was conducted among healthy university students living at Butare, Rwanda (altitude: 1,768 m, barometric pressure: 629 mm Hg) in December 2011. Methods: Venous blood was collected in the morning, after overnight fasting. TSH, total T3 and total T4 hormonal assays were performed in the laboratory of Butare University Teaching Hospital by classical sandwich ELISA technique for TSH and competitive ELISA technique for total T4 and total T3. Results:The results of 111 subjects (65 males and 46 females; mean age: 22 years, age range: 18-28 years) are as follows (mean ± SD): total T3: males: 0.9 ± 0.3 ng/mL, females: 1.3 ± 0.3 ng/mL; total T4: males: 6.4 ± 1.1 µg/dL, females: 9.3 ± 2.2 µg/dL; TSH: males: 1.8 ± 1.2 mIU/L, females: 1.9 ± 1.4 mIU/L. Conclusion: The results of our study compare well with findings of other studies, with a slight increase in serum TSH concentration as compared to sea level values. A comprehensive study needs to be done to establish reference intervals.

Age-Related Changes in Thyroid Function: A Longitudinal Study of a Community-Based Cohort

In cross-sectional studies, serum TSH concentrations increase with age. This has not been examined longitudinally, and it is uncertain whether the TSH increase reflects healthy aging or occult thyroid failure. We measured serum TSH, free T(4), thyroid peroxidase, and thyroglobulin antibodies in 1100 participants in the 1981 and 1994 Busselton Health Surveys and derived a reference group of 908 individuals without thyroid disease or thyroid antibodies. We examined changes in thyroid function longitudinally and, in 781 participants, explored associations with the CAPZB polymorphism rs10917469. At 13 yr follow-up, mean serum TSH increased from 1.49 to 1.81 mU/liter, a change in mean TSH (ΔTSH) of 0.32 mU/liter [95% confidence interval (CI) 0.27, 0.38, P < 0.001], whereas mean free T(4) concentration was unchanged (16.6 vs. 16.6 pmol/liter, P = 0.7). The TSH increase was most marked in the elderly, such that gender-adjusted ΔTSH increased by 0.08 mU/liter (95% CI 0.04, 0.11) for each decade of baseline age. People with higher baseline TSH values had proportionally smaller increases in TSH, with each additional 1.0 mU/liter of baseline TSH associated with a 0.13 mU/liter decrease (age and gender adjusted) in ΔTSH (95% CI 0.09, 0.16). The ΔTSH did not differ significantly by CAPZB genotype. Aging is associated with increased serum TSH concentrations, with no change in free T(4) concentrations. The largest TSH increase is in people with the lowest TSH at baseline. This suggests that the TSH increase arises from age-related alteration in the TSH set point or reduced TSH bioactivity rather than occult thyroid disease.

Prolonged Inappropriate TSH Suppression During Hypothyroidism After Thyroid Ablation in a Patient with Nonautoimmune Familial Hyperthyroidism

Prolonged TSH suppression was reported in a patient with nonautoimmune hyperthyroidism. These observations were made during L-thyroxine treatment and it was not possible to investigate a possible increase in serum TSH concentrations to levels observed in untreated hypothyroidism. We describe nonautoimmune familial hyperthyroidism identified in an Israeli woman, which is remarkable for the prolonged inappropriate TSH suppression after thyroid ablation. After 2 radioiodine treatments for several years, her TSH was always lower than 0.03 mU/l with 1.6 μg/kg/day (100 μg) thyroxine. 14 years after the radioiodine treatments, she discontinued thyroxine for 3.5 months and developed myxoedema with fT4 <6.0 and fT3 1.3 pmol/l and TSH of only 4.4 mU/l, which rose to only 8.6 after TRH. Genomic analysis showed a germline substitution M626I in the TSHR gene. Both exons of the thyroid-releasing hormone receptor revealed no mutations in this gene. Functional in vitro characterization of M626I showed a cell surface expression of 70% compared with the wt (100%), a significant increase of basal activity (5-fold over wt basal), which was confirmed by linear regression analysis (LRA) (slope: M626I=7, wt=1). No TRH-receptor mutation was detected. Therefore, this is the first patient with nonautoimmune hyperthyroidism with unequivocal evidence for inappropriately prolonged TSH suppression documented by a clearly insufficient TSH increase during clinical hypothyroidism. The in vitro characterization of the TSH-receptor mutation did not show any explanations for the prolonged TSH suppression. Therefore, other possible candidate genes remain to be investigated for potential explanations for this prolonged TSH suppression.

Studies on the effects of omeprazole on thyroid function in the rat.

The effects of omeprazole (an H+, K+ -ATPase inhibitor) on thyroid parameters in rats have been examined. SK&F Wistar rats were dosed orally with omeprazole (up to 500 mg kg-1) or vehicle. Treatment for 7 or 14 days resulted in generally decreased plasma T3 concentrations in males (with little change or slight increases in females) and increased serum TSH concentrations (22%-68% increases). No changes were detected in thyroid 125I uptake or organification. Liver 5'-deiodinase activity was decreased in male rats after 7 days treatment. Thyroxine clearance was not altered after a single dose of omeprazole. In-vitro studies showed omeprazole to be only a weak inhibitor of TSH-stimulated 125I organification in cultured porcine thyrocytes. It is concluded that omeprazole has weak effects on the pituitary-thyroid-liver axis, its main action being to inhibit the peripheral deiodination of thyroid hormones.

Relations of Thyroid Function to Body Weight&lt;subtitle&gt;Cross-sectional and Longitudinal Observations in a Community-Based Sample&lt;/subtitle&gt;

Overt hypothyroidism and hyperthyroidism may be associated with weight gain and loss. We assessed whether variations in thyroid function within the reference (physiologic) range are associated with body weight. Framingham Offspring Study participants (n=2407) who attended 2 consecutive routine examinations, were not receiving thyroid hormone therapy, and had baseline serum thyrotropin (TSH) concentrations of 0.5 to 5.0 mIU/L and follow-up concentrations of 0.5 to 10.0 mIU/L were included in this study. Baseline TSH concentrations were related to body weight and body weight change during 3.5 years of follow-up. At baseline, adjusted mean weight increased progressively from 64.5 to 70.2 kg in the lowest to highest TSH concentration quartiles in women (P< .001 for trend), and from 82.8 (lowest quartile) to 85.6 kg (highest quartile) in men (P= .007 for trend). During 3.5 years of follow-up, mean (SD) body weight increased by 1.5 (5.6) kg in women and 1.0 (5.0) kg in men. Baseline TSH concentrations were not associated with weight change during follow-up. However, an increase in TSH concentration at follow-up was positively associated with weight gain in women (0.5-2.3 kg across increasing quartiles of TSH concentration change; P< .001 for trend) and men (0.4-1.3 kg across quartiles of TSH concentration change; P= .007 for trend). Thyroid function (as assessed by serum TSH concentration) within the reference range is associated with body weight in both sexes. Our findings raise the possibility that modest increases in serum TSH concentrations within the reference range may be associated with weight gain.

Serological Evidence of Thyroid Autoimmunity among Schoolchildren in Two Different Socioeconomic Environments

The mechanisms leading to thyroid autoimmunity are largely unknown. Our objective was to assess the role of environment in the development of thyroid autoimmunity. Prevalence of thyroid autoantibodies in two neighboring populations living in completely different socioeconomic circumstances (Russian Karelia and Finland) was studied. We studied two population-based cohorts partly sharing the same ancestry. A total of 532 schoolchildren from Russian Karelia and 532 schoolchildren in Finland matched for age, gender, and season of the blood sampling were included. There were no interventions. The prevalence of thyroid peroxidase antibodies (TPOAb), thyroglobulin antibodies (TGAb) and HLA-DQ alleles was measured. The prevalence of TPOAb was significantly lower in Russian Karelian than in Finnish children (0.4 vs. 2.6%, P=0.006). A similar difference was observed for TGAb (0.6 vs. 3.4%, P=0.002). Finnish girls tested positive for both TPOAb (4.3 vs. 0.4%, P=0.01) and TGAb (5.3 vs. 0.9%, P=0.01) more frequently than Finnish boys. Seven of the 23 tested subjects with signs of thyroid autoimmunity (30%) had increased serum TSH concentrations as a sign of subclinical hypothyroidism. The frequency of HLA genotypes did not differ between the two countries or between autoantibody-positive and -negative subjects. The prevalence of thyroid autoimmunity is lower in Russian Karelia than in Finland. This difference was not related to ethnic background or HLA-DQ alleles. The results support the idea that the Russian Karelian environment, which is characterized by inferior prosperity and standard of hygiene, may provide protection against thyroid autoimmunity.

Effect of PCB 126 on Hepatic Metabolism of Thyroxine and Perturbations in the Hypothalamic-Pituitary-Thyroid Axis in the Rat

The objective of this research was to examine the time- and dose- dependent disturbances in the hypothalamic-pituitary-thyroid (HPT) axis of adult male rats administered a potent coplanar (non-ortho) PCB, 3,3',4,4',5-pentachlorobiphenyl (PCB 126). Adult male Sprague-Dawley rats were administered a single oral bolus dose of 0, 7.5, 75, or 275 microg PCB 126/kg bw dissolved in corn oil. The rats were sacrificed periodically over 22 days. The 7.5-microg/kg dose induced hepatic ethoxyresorufin-O-deethylation EROD activity, but no changes were observed in hepatic uridine diphosphate glucuronyl transferases (UDPGTs) activity or serum TSH, T4, or fT4 concentrations. The two highest doses caused a modest decline in weight gain, induced hepatic EROD and UDPGT activities, increased serum TSH concentrations, and decreased serum T4 and fT4 concentrations. The amount of thyroxine glucuronide formed daily (pM/mg protein) increased linearly with the area-under-the-concentration-curve (AUCC) for PCB 126 in liver (microg/kg/day) and then slowed at the 275-microg/kg PCB 126 dose. Perturbations in the HPT axis were nonlinear with respect to PCB 126 dosing. As expected, an inverse relationship between the AUCC for serum T4 (microg/dl/day) and the AUCC for serum TSH (ng/dl/day) was observed; however, the relationship was highly nonlinear. These data support a mode of action for PCB 126 involving induction of hepatic UDPGTs by the aryl hydrocarbon receptor AhR. However, the dose-response characteristics of the HPT axis are nonlinear and complex, requiring sophisticated tools, such as PBPK models, to characterize dose response.

RhTSH-aided radioiodine ablation and treatment of differentiated thyroid carcinoma: a comprehensive review

Traditionally, withdrawal of thyroid hormone has been used to attain the increase in serum TSH concentrations that are believed to optimize the trapping and retention of radioiodine for diagnostic procedures, thyroid remnant ablation and treatment of patients with differentiated thyroid cancer (DTC). However, withdrawal frequently causes clinical hypothyroidism, with resultant cognitive impairment, emotional dysfunction, physical discomfort, health risks in patients who are elderly, frail or have concomitant illness, and impaired quality of life and ability to work. Recombinant human TSH (rhTSH) was developed to provide TSH stimulation without withdrawal of thyroid hormone and the associated morbidity. rhTSH has been approved as an adjunct for diagnostic procedures in patients with DTC, but is currently an experimental aid in thyroid remnant ablation and the treatment of thyroid tumours. In the period 1997-2004, nearly 30 medical centres worldwide have reported on almost 400 patients with DTC who were given rhTSH in preparation for radioiodine ablation of thyroid remnants or treatment of local tumours of metastatic disease. We have analysed and summarized the findings reported in this literature. Ablation aided by the standard course of rhTSH, two consecutive daily injections of 0.9 mg, had success rates better than 84% in 90 patients given radioiodine activities in excess of 4000 MBq. However, when 1110 MBq was administered, success rates were 81.2% in 16 patients given the standard course of rhTSH and 4-day withdrawal of thyroid hormone around the time of radioiodine administration in one study, but 54% in 70 patients in another study. rhTSH-aided treatment of persistent or recurrent local or metastatic cancer, or both, with from one to six courses of radioiodine 1000-19055 MBq, achieved 2% complete remission, 36% partial response and 27% disease stabilization rates, for a 65% clinical benefit rate, in 115 primarily elderly, late-stage patients for whom responses were reported. Twelve of these patients died as a result of progressive disease or were discharged from hospital into hospice care. Generally, rhTSH was very well tolerated. However, in a minority of patients with central nervous system, spinal or bone metastases, or bulky thyroid remnant or neck lesions with or without poor pulmonary reserve, administration of rhTSH, like thyroid hormone withdrawal, was found to stimulate expansion of the tumour, with ensuing compression of key anatomical structures and neurological, respiratory or other clinical complications. The rapid onset, response to glucocorticoids and radiological findings of peritumoural oedema or, less commonly, haemorrhage in the published cases, strongly suggest that the tumour expansion was the result of swelling rather than growth. As in the case of thyroid hormone withdrawal, special attention and glucocorticoid premedication are thus warranted when rhTSH is given to patients known or suspected to have the above characteristics. Dosimetric data suggest that whole-body and whole-blood radioiodine clearance may be faster in euthyroid patients after administration of rhTSH. In theory, the faster clearance could allow, or demand, increased radioiodine activities when rhTSH is used, but clinical data to date suggest that this may be unnecessary. The faster clearance also might result in safety or convenience benefits with the use of rhTSH, such as decreased exposure of extrathyroid areas to radiation, and shorter hospital stays. In conclusion, in preliminary results from open-label studies, both rhTSH-aided tumour ablation and treatment have been well tolerated and have shown efficacy in substantial proportions of patients. rhTSH-aided ablation merits further study. rhTSH-aided treatment may be preferred in patients who are at greater risk of hypothyroid complications from withdrawal of thyroid hormone or are unable to produce sufficient endogenous TSH, and warrants additional investigation in younger patients at earlier stages of thyroid cancer.

Hypothyroidism in thyroid transcription factor 1 haploinsufficiency is caused by reduced expression of the thyroid-stimulating hormone receptor.

Humans expressing one allele of the thyroid transcription factor 1 (TTF1) gene have neurological symptoms and increased serum TSH with variable degrees of hypothyroidism. Ttf1+/- mice have also poor coordination and increased serum TSH concentration (205 +/- 22 vs. 92 +/- 12 mU/liter; P < 0.001) and slightly lower T4 (46 +/- 3 vs. 63 +/- 6 nmol/liter; P < 0.02) as compared with Ttf1+/+ mice. To determine whether the hypothyroidism is of central or primary origin, we examined the bioactivity of TSH, thyroidal response to exogenous TSH and the expression of genes regulated by TTF1. TSH bioactivity was normal, but T4 response to a low but not high dose of TSH was significantly reduced in the Ttf1+/- mice (5.5 +/- 2.2 vs. 15.3 +/- 4.1 nmol/liter; P < 0.03), indicating a reduced thyroidal response. Thyroid mRNAs were measured by real-time PCR (Ttf1+/+ littermates = 100%). Ttf1+/- mice had half the levels of TTF1 mRNA (54 +/- 9; P < 0.01) and protein, confirming their haploinsufficiency. Significantly lower levels of mRNAs were observed for two of the three genes with TTF1 cis elements: TSH receptor (TSHr, 57 +/- 4%; P < 0.002), thyroglobulin (63 +/- 7%; P < 0.005), but not thyroid peroxidase (81 +/- 12%; P > 0.05). No significant difference between the two genotypes was found for Pax8, sodium iodide symporter, and iodothyronine deiodinase 1. These results show that Ttf1 haploinsufficiency causes a reduction in the expression of TSHr and thyroglobulin, genes with TTF1 binding sites in their promoter regions. The low TSHr is only partially compensated by an increase in TSH secretion because T4 remains mildly reduced. However, administration of a larger amount of TSH obliterates the response differences by saturating a reduced amount of receptor.

The Sardinian Autoimmunity Study: 3. Studies on circulating antithyroid antibodies in Sardinian schoolchildren: relationship to goiter prevalence and thyroid function.

The relationship among iodine intake, goiter prevalence, and thyroid autoimmunity remains controversial. In the present article, we report the prevalence of antithyroid antibodies (ATA) in relation to iodine intake, frequency of goiter, and thyroid function in a large group of Sardinian schoolchildren living in areas with borderline iodine sufficiency, or mild to moderate iodine deficiency. A total of 8,040 schoolchildren (4,194 males, 3,846 females, ages 6-15 years) from 29 communities were examined between 1986-1994. Thyroid size was assessed by palpation, according to the Pan American Health Organization (PAHO) criteria. In all cases antimicrosomal (MAb) or antithyroid peroxidase antibodies (TPOAb) and thyrotropin (TSH) were assayed. Urinary iodine was determined in a subgroup of 820 children. ATA was detected in 235 (2.92%) sera (88 males, 2.12%; 147 females, 3.82%; chi2 = 20.41, p < 0.0001). ATA prevalence ranged between 0.0%-7.3% in the 29 communities without any geographical correlation with goiter prevalence and urinary iodine excretion. However, ATA was more frequently detected in goitrous children, especially in females. The presence of ATA was not age-dependent in males, whereas a significant increase of ATA was observed in females older than 11 years of age. Seventy-seven (0.96%) children showed borderline to slightly increased serum TSH (>5.2-32 mU/L). Increased serum TSH concentration was more frequently found in children with ATA, especially at higher titers. In summary, our study in Sardinian schoolchildren indicates: (1) ATA display geographical heterogeneity, which seems to be unrelated to goiter prevalence and/or to iodine supply; (2) ATA are more frequently detected in females older than 11 years of age, suggesting that puberty has a role in determining the predominance in females of thyroid autoimmunity; (3) although most goitrous children are ATA-negative, the prevalence of ATA is increased in children with enlarged glands; (4) ATA is associated with an increased prevalence of subclinical hypothyroidism.

Thyroid Function and Intellectual Development of Infants Nursed by Mothers Taking Methimazole

For many years, breast-feeding was forbidden if antithyroid drugs were being used. Recently, limited studies have shown the relative safety of propylthiouracil and methimazole (MMI). It is not known whether MMI therapy of lactating mothers for 1 yr is safe for breast-fed infants and does not cause alterations in thyroid function and intellectual development. Between 1988 and 1998, 139 thyrotoxic lactating mothers and their infants were studied. Fifty-one thyrotoxic lactating mothers were treated with MMI during pregnancy, and MMI was continued during breast-feeding. Eighty-eight mothers were given 10 mg MMI (n = 46) or 20 mg MMI (n = 42) daily for 1 month, 10 mg daily for the second month, and 5–10 mg daily thereafter. Serum T4, T3, and TSH concentrations were measured in thyrotoxic lactating mothers and their infants, before and at 1, 2, 4, 8, and 12 months. Serum MMI was measured in the infants of thyrotoxic lactating mothers taking 20 mg MMI. Thyroid function, urinary iodine, thyroid antibodies, intelligence quotient (IQ), verbal and functional components (Wechsler and Goodenough tests) were performed on 14 children of thyrotoxic lactating mothers between 48 and 74 months of age and on 17 controls. Mean ± SD of FT4I in thyrotoxic lactating mothers treated with 10 mg MMI for 1 month decreased from 19.4 ± 4.1 to 11.6 ± 4.4 and from 20.5 ± 4.7 to 9.8 ± 1.5 when treated with 20 mg MMI. Values for FT3I decreased from 462 ± 52 to 194 ± 52 with 10 mg MMI and from 481 ± 92 to 171 ± 38 with 20 mg MMI. FT4I and FT3I were normal from the third to the twelfth months. In all infants FT4I, FT3I, and TSH concentrations were normal before and up to 12 months of MMI therapy in their lactating mothers. The lowest T4 and T3 values were 108 and 1.87 nmol/L, and the highest TSH value was 4.0 mU/L. Serum MMI levels in infants were less than 0.03 μg/mL. Six mothers receiving 20 mg MMI had increased serum TSH concentrations ranging from 26 – 135 mU/L after 1 month of treatment. Their infants were euthyroid with serum TSH values less than 2.6 mU/L. At 48–74 months of age, height, weight, FT4I, FT3I, TSH, and antithyroid antibody titers were not different than controls. The mean IQ was 107 ± 14 vs. 106 ± 16 (Goodenough test) and 103 ± 10 vs. 103 ± 16 (Wechsler test) for infants of thyrotoxic lactating mothers and control infants, respectively. Similarly, there was no difference in verbal and performance IQ and their components between infants of thyrotoxic lactating mothers and control children. No deleterious effects occur in thyroid function and physical and intellectual development of breast-fed infants whose lactating mothers were treated with doses of MMI up to 20 mg daily.