Euthyroid Volunteers Research Articles

Characterization of the thyroid hormones level in urine by liquid chromatography coupled to mass spectrometry focus in the antidoping field.

This paper aims to study the metabolism of thyroid hormones (TH) in urine by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The method was applied to samples collected before and after the administration of sodium triiodothyronine (T3) and sodium levothyroxine (T4) to a euthyroid volunteer and to samples of athletes declaring and not declaring thyroid supplementation. Samples were analyzed by LC-MS/MS after enzymatic hydrolysis, liquid-liquid, and solid-phase extractions. Ratios between T3/thyronine and T4/3,3'-T2 may be used for the detection of the administration of exogenous T3 in urine. Meanwhile, 3-T1 concentrations may be used to detect exogenous T4 administration. Nevertheless, these markers may not work properly in hypothyroid population, as athletes seem to be. The levels of T3 and T4 of athletes were lower than those of a euthyroid state even when they are under administration of TH supplements. The HTP axis high efficiency does not allow observing differences between athletes who do not declare and those who declare having used TH supplementation by direct measurements of T3 and T4 in urine. The detection of TH administration in urine (triiodothyronine and levothyroxine) may work when dealing with euthyroid individuals. Nevertheless, in individuals with hypothyroidism where the tendency is toward the maintenance of homeostasis, and it may be not possible to detect their consumption by applying cut-off values.

Hypothyroidism and subclinical hypothyroidism are associated with fatty pancreas (Non-Alcoholic Fatty Pancreas Disease).

Increasing visceral fat deposition with raised prevalence of obesity and metabolic syndrome is associated with many adverse conditions, especially cardiovascular diseases and diabetes. Although there are many studies that investigate hepatic steatosis in hypothyroidism and subclinical hypothyroidism, to the best of our knowledge, there is no study investigating its relationship with pancreatic steatosis. In the present study, the purpose was to investigate this relationship. Physical and biochemical characteristics of 30 hypothyroid, 30 subclinical hypothyroid, and 30 euthyroid volunteers were recorded in this cross-sectional study. Liver and pancreatic steatosis were evaluated with ultrasonography. It was found that pancreatic steatosis was increased in hypothyroid and subclinical groups when compared to the control group, and hepatic steatosis was increased in the subclinical group when compared to the control group (steatosis; p=0.002, p=0.004, p=0.001, p=0.002, p=0.002, p=0.004). Pancreatic steatosis was positively correlated with age, hepatic steatosis, height, weight, BMI, waist circumference, hip circumference, hemoglobin, Insulin, alanine aminotransferase, Triglyceride, Creatinine, and gamma-glutamyltransferase and was negatively correlated with total cholesterol, high-density lipoproteins. The prevalence of pancreatic steatosis was found to be increased in hypothyroidism and subclinical hypothyroidism when compared with the euthyroid control group.

Free Thyroxine Levels are Associated with Cold Induced Thermogenesis in Healthy Euthyroid Individuals.

Thyroid hormone (TH) is an important regulator of mammalian metabolism and facilitates cold induced thermogenesis (CIT) in brown adipose tissue (BAT). Profound hypothyroidism or hyperthyroidism lead to alterations in BAT function and CIT. In euthyroid humans the inter-individual variation of thyroid hormones is relatively large. Therefore, we investigated whether levels of free thyroxine (T4) or free triiodothyronine (T3) are positively associated with CIT in euthyroid individuals. We performed an observational study in 79 healthy, euthyroid volunteers (mean age 25.6 years, mean BMI 23.0 kg · m-2). Resting energy expenditure (REE) was measured by indirect calorimetry during warm conditions (EEwarm) and after a mild cold stimulus of two hours (EEcold). CIT was calculated as the difference between EEcold and EEwarm. BAT activity was assessed by 18F-FDG-PET after a mild cold stimulus in a subset of 26 participants. EEcold and CIT were significantly related to levels of free T4 (R2 = 0.11, p=0.0025 and R2 = 0.13, p=0.0011, respectively) but not to free T3 and TSH. Cold induced BAT activity was also associated with levels of free T4 (R2 = 0.21, p=0.018). CIT was approximately fourfold higher in participants in the highest tertile of free T4 as compared to the lowest tertile. Additionally, free T4 was weakly, albeit significantly associated with outdoor temperature seven days prior to the respective study visit (R2 = 0.06, p=0.037). These finding suggests that variations in thyroid hormone levels within the euthyroid range are related to the capability to adapt to cool temperatures and affect energy balance.

Evaluation of anxiety and depression in patients with thyroid function disorder.

OBJECTIVES We aim to determine the anxiety and depression levels of patients treated for hypothyroidism who assumed euthyroid status. These patients also frequently attend family medicine outpatient clinics. METHODS This study was conducted on 76 euthyroid volunteer participants (patient groups) who were treated for hypothyroidism and followed-up and 22 healthy volunteers (control group). Questionnaires were administered to all participants to assess anxiety and depression levels. The Beck Depression Inventory (BDI) and Beck Anxiety Inventory (BAI) were applied to all the groups. In addition, BAI sub-parameters were evaluated in detail. RESULTS At least mild depression was detected in 54.5% of the first group, 41.7% of the second group, and 33.3% of the third group. When the BDI and BAI total scores of the participants in different groups were compared, statistically significant differences were determined. Statistically significant results were detected related to different BAI sub-parameters between the patient groups and in comparison to the fourth group. CONCLUSIONS We found that patients were predisposed to anxiety and depression even if they were euthyroid. When the sub-parameters of BAI were evaluated in detail, we observed that the duration of the disease significantly affected some anxiety-related symptoms.

3,5-T2-A Janus-Faced Thyroid Hormone Metabolite Exerts Both Canonical T3-Mimetic Endocrine and Intracrine Hepatic Action.

Over the last decades, thyroid hormone metabolites (THMs) received marked attention as it has been demonstrated that they are bioactive compounds. Their concentrations were determined by immunoassay or mass-spectrometry methods. Among those metabolites, 3,5-diiodothyronine (3,5-T2), occurs at low nanomolar concentrations in human serum, but might reach tissue concentrations similar to those of T4 and T3, at least based on data from rodent models. However, the immunoassay-based measurements in human sera revealed remarkable variations depending on antibodies used in the assays and thus need to be interpreted with caution. In clinical experimental approaches in euthyroid volunteers and hypothyroid patients using the immunoassay as the analytical tool no evidence of formation of 3,5-T2 from its putative precursors T4 or T3 was found, nor was any support found for the assumption that 3,5-T2 might represent a direct precursor for serum 3-T1-AM generated by combined deiodination and decarboxylation from 3,5-T2, as previously documented for mouse intestinal mucosa. We hypothesized that lowered endogenous production of 3,5-T2 in patients requiring T4 replacement therapy after thyroidectomy or for treatment of autoimmune thyroid disease, compared to production of 3,5-T2 in individuals with intact thyroid glands might contribute to the discontent seen in a subset of patients with this therapeutic regimen. So far, our observations do not support this assumption. However, the unexpected association between high serum 3,5-T2 and elevated urinary concentrations of metabolites related to coffee consumption requires further studies for an explanation. Elevated 3,5-T2 serum concentrations were found in several situations including impaired renal function, chronic dialysis, sepsis, non-survival in the ICU as well as post-operative atrial fibrillation (POAF) in studies using a monoclonal antibody-based chemoluminescence immunoassay. Pilot analysis of human sera using LC-linear-ion-trap-mass-spectrometry yielded 3,5-T2 concentrations below the limit of quantification in the majority of cases, thus the divergent results of both methods need to be reconciliated by further studies. Although positive anti-steatotic effects have been observed in rodent models, use of 3,5-T2 as a muscle anabolic, slimming or fitness drug, easily obtained without medical prescription, must be advised against, considering its potency in suppressing the HPT axis and causing adverse cardiac side effects. 3,5-T2 escapes regular detection by commercially available clinical routine assays used for thyroid function tests, which may be seriously disrupted in individuals self-administering 3,5-T2 obtained over-the counter or from other sources.

Re-establishment of normal radioactive iodine uptake reference range in the era of universal salt iodization in the Indian population.

Background & objectives:The reference radioactive iodine uptake (RAIU) values established in the 1970s in the era of widespread iodine deficiency were relatively high. Now, after four decades of successful Universal Salt Iodization (USI) programme in India, there is a need to re-establish these reference ranges. The present study was aimed to quantify the two-hour and 24-h RAIU values in iodine sufficient euthyroid individuals and validate the results in Graves’ and Hashimoto's thyroiditis patients.Methods:In this prospective study conducted from April 2012 to September 2013, euthyroid volunteers who consented for the investigations were enrolled in the study. Treatment-naive Graves’ disease and Hashimoto's thyroiditis patients were recruited from the outpatient clinic. The investigations included neck ultrasonography, thyroid function tests, thyroglobulin (Tg), anti-Tg and anti-thyroid peroxidase antibody and urinary iodine concentration.Results:Three different groups comprising 110 euthyroid volunteers, 38 Graves’ and 17 Hashimoto's thyroiditis patients were enrolled in the study. The mean 2-h RAIU values for the euthyroid group, Hashimoto's thyroiditis and Graves’ patients were 3.83±2.77, 4.22±3.41 and 32.67±15.93 per cent, and mean 24-h RAIU values were 12.75±5.51, 11.66±9.55 and 61.85±12.9 per cent, respectively. The mean thyroid volumes were 7.63±2.72, 7.81±1.67 and 20.76±12.56 ml for the euthyroid, Hashimoto's thyroiditis and Graves’ disease groups and the mean spot urinary iodine concentrations were 9.0, 7.8 and 13.9 µg/dl in the three groups, respectively. The new reference range (95% confidence interval) for two-hour was 1-7 per cent and 24-h was 7-18 per cent.Interpretation & conclusions:Compared to the previous values, there was a considerable decrease in the RAIU values in euthyroid individuals. This was further corroborated with increase in the urinary iodine concentration and decrease in thyroid volume, attributed to successful USI programme. Further studies with a large sample from different parts of India need to be done to confirm these findings.

Assessment of functional lung impairment in patients with thyroid disorders

Many thyroid diseases can lead to pulmonary problems. Hypothyroidism reduces respiratory drive and can cause obstructive sleep apnea, pleural effusion, skeletal muscle myopathy, and decreased carbon monoxide diffusing capacity, whereas hyperthyroidism increases respiratory drive and can cause dyspnea on exertion. Thus, the aim of this study was to evaluate and compare the frequency of clinical presentations, the extent of lung functional endurance (spirometric and diffusion lung capacity), and arterial blood gases affection between patients with hypothyroidism and hyperthyroidism when compared with normal euthyroid volunteers and find out who could compromise the respiratory system more. This study included 90 participants (30 patients with hyperthyroidism, 30 patients with hypothyroidism, and the remaining 30 were normal healthy volunteers as control) referred from the Endocrinology and Internal Medicine Departments in Ain Shams University Hospitals and Misr University for Science and Technology according to their serum free thyroid hormone 3, free thyroid hormone 4, and thyroid-stimulating hormone values. Spirometric function tests and diffusing capacity of the lung for carbon monoxide evaluation were performed for all participants. Respiratory symptoms were more frequent in hypothyroid than in hyperthyroid patients, especially cough, sputum production, and chest wheezes. All spirometric functional parameters and respiratory muscle function were decreased (whether or not significant) among patients with hypothyroidism and hyperthyroidism compared with normal euthyroid controls. More statistically significant respiratory functional impairment was noticed among patients with hypothyroidism than among those with hyperthyroidism. Diffusion was more affected in the hypothyroidism group than in the hyperthyroid group, but it was statistically nonsignificant. A statistically significant increase in partial carbon dioxide pressure was observed among patients with hypothyroidism than in patients in hyperthyroidism (However, there was a statistically significant decrease in partial oxygen pressure and pH in patients with hypothyroidism than in those with hyperthyroidism.). Although oxygen saturation was lower in hypothyroidism, it was statistically nonsignificant. Hypothyroidism causes greater respiratory system endurance compared with hyperthyroidism. Early diagnosis and hormonal replacement may be of value.

Relationship of TSH with atherosclerosis-related factors in subclinical hypothyroidism

Two hundred and fifty patients with subclinical hypothyroidism(SCH)and 120 euthyroid volunteers were recruited for the study, SCH patients were stratified into 2 groups according to TSH levels(group A: TSH 10 mIU/L). All subjects were examined for clinical characteristics, thyroid profile, lipid profile, and biomarkers of early atherosclerosis. Patients in group B received L-thyroxine replacement treatment to achieve euthyroidism. After 6 months of stable euthyroidism all measurements were repeated. SCH patients had higher levels of total cholesterol(TC), low-density lipoprotein-cholesterol(LDL-C), asymmetric dimethyl arginine(ADMA), carotid artery intima media thickness(CIMT), thromboxane B2(TXB2), and C-reactive protein(CRP)but with lower nitric oxide(NO)level compared with euthyroid subjects. Levels of TC, LDL-C, CIMT, TXB2, and ADMA decreased, and NO level increased significantly after 6 months of euthyroidism. TSH was positively correlated with TC, LDL-C, CIMT, ADMA, and TXB2; and negatively correlated with NO. Based on multivariate regression analysis, TSH was an independent influential factor of CIMT and NO. We conclude that raised TSH is an important risk factor of atherosclerosis in SCH. (Chin J Endocrinol Metab, 2015, 31: 133-135) Key words: Hypothyroidism; Thyroid-stimulating hormone; Atherosclerosis; L-thyroxine

High thyroid-stimulating hormone level is associated with the risk of developing atherosclerosis in subclinical hypothyroidism.

The aim of our study was to assess the potential role of thyroid-stimulating hormone (TSH) in the risk of developing atherosclerosis in subclinical hypothyroidism (SCH). A cohort of 240 SCH patients and 150 euthyroid volunteers were recruited for the study. SCH patients were stratified into 2 groups according to TSH levels (group A: TSH<10 mIU/l; group B: TSH>10 mIU/l). All subjects were examined for clinical and biochemical parameters. Visfatin, omentin-1, and circulating endothelial biomarkers were measured. Patients in group B received l-thyroxine replacement to achieve euthyroidism; after 6 months of euthyroidism all measurements were repeated. Patients with SCH had higher total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and C-reactive protein (CRP) levels and lower nitric oxide (NO) and omentin-1 levels compared to euthyroid subjects (all p<0.05). TC, LDL-C, and CRP decreased significantly, while NO and omentin-1 levels increased significantly after l-thyroxine replacement. Based on multivariate liner stepwise regression analysis, omentin-1 was independently correlated with BMI and TSH; NO was independently correlated with age, TSH, LDL-C, and omentin-1. High TSH level contributes to endothelial dysfunction in SCH, while TSH-induced decrease of omentin-1 provides a new link between SCH and atherogenic risk.

Relationship between liver function tests and thyroid hormones in thyroid disorders

To evaluated the effect of thyroid dysfunction on liver function tests and if there is any correlation between them. A total of 68 subjects (40 hyperthyroid and 28 hypothyroid) between the ages of 20-60 years old and 40 healthy euthyroid volunteers of the same age groups were studied. Plasma albumin, bilirubin (total and conjugated), thyroxine (T4), triiodothyronine (T3), thyroid stimulating hormone (TSH); activities of aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma glutamyltransferase (GGT) were estimated in the plasma of the participants. Plasma concentration of Total .bilirubin and liver enzyme activities increased significantly in both hyperthyroid and hypothyroid subjects. The positive correlations between thyroid hormones and liver enzymes in hyperthyroid subjects were negative in hypothyroid subjects and vice-visa. It can be concluded that both hyperthyroidism and hypothyroidism altered liver function tests. It is thus recommended that liver function tests interpretation in thyroid dysfunction should be with caution.

Lean body mass-based levothyroxine replacement in young athyrotic patients with differentiated carcinoma of thyroid

Objective:The objective of this study was to optimize dose of levothyroxine (LT4) based on lean body mass (LBM) in young athyrotic patients with differentiated carcinoma of thyroid (DCT) which has not been properly addressed in Bangladesh before.Materials and Methods:Sixty patients with DCT (age, range: 20-39 years) having total thyroidectomy followed by radioiodine ablative therapy (RIT) and 23 euthyroid volunteers were recruited. Clinical, biochemical parameters were obtained from all patients after 2 months of RIT and on LT4 replacement at a dose of 200 μg/day as first follow up visit and also from control subjects. Then 60 patients were divided into two groups consisting of 30 patients each. Patients of Group-I received LT4 replacement based on LBM measured by dual energy X-ray absorptiometry (DXA) and Group-II continued LT4 replacement in conventional dose. Patients of both groups were assessed again for same parameters at 6 to 12 months at the second visit.Results:Optimized dose of LT4 based on LBM by DXA (131 ±23 μg/day) significantly reduced thyroid hormones and kept thyroid stimulating hormone (TSH) in expected levels in patients of Group-I at the second visit compared to patients of Group-II who continued conventional LT4 dose (200 μg/day). Hyperthyroid symptom scale (HSS) was significantly reduced to 2 ± 1 in patients of Group-I but not in patients of Group-II, HSS, 8 ±1 (P > 0.001).Conclusion:Optimization of LT4 dose based on LBM can avoid chronic exposure of mild excess of thyroid hormone in young patients with low risk DCT.

Recurrent IVF failure: other factors

IVF failure is a problem for a couple in the singular but can be a tragedy in the plural. Recurrent IVF failure has multiple known causes but many which are not routinely considered as part of the posttreatment analysis. The reason is there are several causes associated with lifestyle and other causes related to pre-existing conditions that have only a tenuous or no apparent connection to fertility. This article examines the impact of obesity, cigarette smoke, uterine anatomy, body mass index, thyroid dysfunction, immune factors, the hereditary and acquired thrombophilias, and embryo transfer technique on recurrent IVF failure.

Increased carotid arterial stiffness in subclinical hypothyroidism

Objective Arterial stiffness is involved in the pathophysiology of cardiovascular disease, and subclinical hypothyroidism (SCH) is associated with increased risk of atherosclerosis. The present study was designed to examine whether SCH is associated with an increase in carotid arterial stiffness. Methods The carotid arterial stiffness parameter in 93 patients with SCH and 90 sex- and age-matched euthyroid volunteers was evaluated using a color Doppler ultrasound machine implemented with a high-resolution echo-tracking system. Results The participants with SCH had higher total cholesterol, LDL-cholesterol and highly sensitive C-reactive protein (hsCRP) levels than those who were euthyroid. Furthermore, carotid arterial stiffness β (β index) was significantly higher in SCH patients than in normal controls, and β index was significantly positively correlated with age, smoking index, diastolic blood pressure, systolic blood pressure, TSH and hsCRP and significantly negatively correlated with pulse rate in subclinical hypothyroid patients. Conclusions Subclinical hypothyroidism is associated with preclinical vascular alteration, characterized by increased carotid arterial stiffness values, which have been shown to be related to the hsCRP and TSH.

Reference Intervals for Serum Thyrotropin: Dependence on the Population Investigated

In order to elucidate possible differences of reference intervals in various populations, serum basal thyrotropin (TSH) was measured in euthyroid healthy volunteers (N = 170), in thyroid out-patients (N = 215), in geriatric (N = 354) and in seriously ill (N = 32) patients. The results, except in the healthy control subjects, were compared to the TSH responses (delta TSH) in the Thyrotropin Releasing Hormone test. Normal ranges calculated from the basal TSH of the euthyroid groups of different age were similar. There was a significant positive correlation of basal to delta TSH in all groups but the regression equations expressing the qualitative connection of basal and delta TSH were rather different. The basal TSH cut off point predicting a positive TRH-test (i.e. euthyroidism) with more than 95% probability was higher in the geriatric groups (greater than 0.7 mU/l versus greater than 0.4 mU/l in the other groups). In thyroid out-patients and geriatric patients a measurable (greater than 0.1 mU/l) basal TSH indicated measurable delta TSH (thus excluding clinical hyperthyroidism), while in seriously ill patients only a basal TSH greater than 0.2 mU/l was reliably predictive in this respect. Thus, various populations have different reference intervals for TSH. This fact must be considered when the sensitive TSH is used in different populations as the primary screening parameter for thyroid dysfunctions.

TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T4Bioequivalence

FDA Guidance for pharmacokinetic (PK) testing of levothyroxine (L-T(4)) for interbrand bioequivalence has evolved recently. Concerns remain about efficacy and safety of the current protocol, based on PK analysis following supraphysiological L-T(4) dosing in euthyroid volunteers, and recent recalls due to intrabrand manufacturing problems also suggest need for further refinement. We examine these interrelated issues quantitatively, using simulated what-if scenarios testing efficacy of a TSH-based protocol and tablet stability and absorption, to enhance precision of L-T(4) bioequivalence methods. We use an updated simulation model of human thyroid hormone regulation quantified and validated from data that span a wide range of normal and abnormal thyroid system function. Bioequivalence: We explored a TSH-based protocol, using normal replacement dosing in simulated thyroidectomized patients, switching brands after 8 weeks of full replacement dosing. We simulated effects of tablet potency differences and intestinal absorption differences on predicted plasma TSH, T(4), and triiodothyronine (T(3)) dynamics. Stability: We simulated effects of potency decay and lot-by-lot differences in realistic scenarios, using actual tablet potency data spanning 2 years, comparing the recently reduced 95-105% FDA-approved potency range with the original 90-110% range. A simulated decrease as small as 10-15% in L-T(4) or its absorption generated TSH concentrations outside the bioequivalence target range (0.5-2.5 mU/L TSH), whereas T(3) and T(4) plasma levels were maintained normal. For a 25% reduction, steady-state TSH changed 300% (from 1.5 to 6 mU/L) compared with <25% for both T(4) and T(3) (both within their reference ranges). Stability: TSH, T(4), and T(3) remained within normal ranges for most potency decay scenarios, but tablets of the same dose strength and brand were not bioequivalent between lots and between fresh and near-expired tablets. A pharmacodynamic TSH-measurement bioequivalence protocol, using normal L-T(4) replacement dosing in athyreotic volunteers, is likely to be more sensitive and safer than current FDA Guidance based on T(4) PK. The tightened 95-105% allowable potency range for L-T(4) tablets is a significant improvement, but otherwise acceptable potency differences (whether due to potency decay or lot-by-lot inconsistencies) may be problematic for some patients, for example, those undergoing high-dose L-T(4) therapy for cancer.

Bone and heart abnormalities of subclinical hyperthyroidism in women below the age of 65 years

The objective of the present study was to evaluate bone and cardiac abnormalities and symptoms and signs of thyroid hormone excess in women with subclinical hyperthyroidism (SCH) aged < 65 years. Forty-eight women with SCH were evaluated. The control group consisted of 48 euthyroid volunteers. The mean symptom rating scale score was significantly higher in patients. Cardiac involvement, both morphological and affecting systolic and diastolic functions, was also observed in patients. Women with SCH showed a significant increase in serum markers of bone formation and resorption. In addition, bone mineral density (BMD) was lower in the femoral neck but not in the lumbar spine in patients before menopause, whereas a lower BMD was observed at both sites in postmenopausal patients. SCH is not completely asymptomatic in women aged < 65 years, and is associated with heart abnormalities and with increased bone turnover and reduced BMD even before menopause.

Bioequivalence of two levothyroxine tablet formulations without and with mathematical adjustment for basal thyroxine levels in healthy Argentinian volunteers: A single-dose, randomized, open-label, crossover study

Background: Levothyroxine has a narrow therapeutic index; therefore, precise and accurate assessment of the bioequivalence of different levothyroxine products is critical. Bioavailability estimates of levothyroxine formulations might be affected by baseline concentrations of the hormone.Objectives: The aim of this study was to assess the bioequivalence of 100 µg of a test (T4 Montpellier® 100, Química Montpellier S.A., Buenos Aires, Argentina) and reference (Synthroid®, Abbott Laboratories, Abbott Park, Illinois) formulation of levothyroxine. We also compared 2 methods of levothyroxine measurements: without and with baseline correction for endogenous levothyroxine.Methods: This randomized, open-label, 2-sequence, crossover study with a 65-day washout period was carried out in healthy, white, euthyroid volunteers following a single dose of sodium levothyroxine 600 µg. Blood samples were collected at 30 and 15 minutes prior to administration, and 0 (baseline), 0.5, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 10, 12, 24, and 48 hours to determine thyroxine; serum thyrotropin (TSH) concentrations were determined 30 minutes before administration and 48 hours after administration. Serum concentrations of thyroxine were determined through radioimmunoassay and serum TSH concentrations were determined by a validated 2-site immunoradiometric assay. The formulations are considered to be equivalent if the 90% CI ratios for Cmax and AUC0-last are within 80% to 125%, per the US Food and Drug Administration (FDA). Adverse event monitoring was performed throughout the study by assessing clinical parameters (eg, blood pressure, electrocardiogram) and patient reports.Results: A total of 24 volunteers (16 male, 8 female; mean [SD] age, 30.2 [4.6] years [range, 21-40 years]; mean [SD] weight, 71.71 [7.52] kg [range, 58-83 kg]) were included in the study. Without adjustment for baseline levels of endogenous levothyroxine, geometric mean Cmax for the test and reference formulations were 8.92 and 9.39 µg/dL, respectively; AUC0-last values were 368.40 and 383.37 µg/mL · h-1. The 90% CI of the geometric mean for the percent ratios (test: reference) of Cmax and AUC0-last were 95.1% (90% CI, 91.9–98.3) and 96.1% (90% CI, 94.0–98.2), respectively. With adjustment for baseline levels of endogenous levothyroxine, the geometric mean Cmax for the test and reference formulations were 3.16 and 3.39 µg/dL, respectively; AUC0-last values were 88.33 and 95.60 µg/mL · h-1. Despite performing the adjustment, the 90% CI of the geometric mean for Cmax and AUC0-last test:reference ratios were 93.1% (90% CI, 84.9–102.2) and 92.4% (90% CI, 85.2–100.2), respectively. No significant between-group differences were found with regard to pharmacokinetic parameters. No adverse events were observed or reported.Conclusion: The results of this study suggest that the test formulation was bioequivalent to the reference formulation of levothyroxine in these healthy volunteers, according to the US FDA definition of bioequivalence. This was supported by the analysis of concentration-time profiles without and with correction for basal endogenous levothyroxine.

CTLA4 Gene Polymorphisms in Children and Adolescents with Autoimmune Thyroid Diseases

Two common forms of autoimmune thyroid diseases are Graves' disease and Hashimoto's thyroiditis. Cytotoxic T lymphocyte antigen 4 (CTLA4) encoded by the CTLA4 gene on chromosome 2q33 plays a role in susceptibility to Graves' disease and is probably important also for Hashimoto's thyroiditis as well as for the other endocrine autoimmune disorders. The CTLA4 locus is the only nonhuman leukocyte antigen locus that has been found in association with Graves' disease repeatedly. Particularly, association of three polymorphic markers of CTLA4 gene, namely, C(-318)T, A49G, and (AT)n dinucleotide repeat, with Graves' disease was demonstrated in most of the population-based investigations. On the other hand, there are few studies to reveal the association of these markers with Hashimoto's thyroiditis. A49G polymorphism was proposed to be associated with Hashimoto's thyroiditis, and C(-318)T was suggested to be not associated. The patient groups consisted of 88 patients (10 males and 78 females; mean age: 14.5 +/- 3.2 years [4.6-21.0 years]) with a previous diagnosis of Hashimoto's thyroiditis and 112 euthyroid volunteers (51 males and 61 females; mean age: 14.1 +/- 2.9 years [5.2-18 years]). The frequency of A/G (A49G) genotype was high and statistically significant in patients with Hashimoto's thyroiditis in comparison with the control group. Although the frequency of C/T [C(-318)T] genotype is not significantly high in children with Hashimoto's thyroiditis according to the control group, the risk of Hashimoto's thyroiditis in A/G genotype group was 4.66 times greater than the group with A/A genotype. In this study, we documented that the A49G polymorphism might increase the susceptibility for Hashimoto's thyroiditis.

Randomized controlled trial of the effect of selenium supplementation on thyroid function in the elderly in the United Kingdom

Background:Thyroid function depends on the essential trace mineral selenium, which is at the active center of the iodothyronine deiodinase enzymes that catalyze the conversion of the prohormone thyroxine (T4) to the active form of thyroid hormone, triiodothyronine (T3). Objective:Because selenium intake in the United Kingdom has fallen during the past 25 y, we wanted to determine whether current selenium status might be limiting conversion of T4 to T3 in the elderly, in whom marginal hypothyroidism is relatively common. Design:We investigated the effect of selenium supplementation in a double-blind, placebo-controlled trial in 501 elderly UK volunteers. Similar numbers of men and women from each of 3 age groups, 60–64 y, 65–69 y, and 70–74 y, were randomly allocated to receive 100, 200, or 300 μg Se/d as high-selenium yeast or placebo yeast for 6 mo. As part of the study, plasma selenium, thyroid-stimulating hormone, and total and free T3 and T4 were measured. Data from 368 euthyroid volunteers who provided blood samples at baseline and 6 mo were analyzed. Results:Although selenium status at baseline correlated weakly with free T4 (r = −0.19, P < 0.001) and with the ratio of free T3 to free T4 (r = 0.12, P = 0.02), we found no evidence of any effect of selenium supplementation on thyroid function, despite significant increases in plasma selenium. However, baseline plasma selenium in our study (x̄: 91 μg/L) was somewhat higher than in previous supplementation studies in which apparently beneficial effects were seen. Conclusion:We found no indication for increasing selenium intake to benefit T4 to T3 conversion in the elderly UK population.

Carotid integrated backscatter analysis in patients with subclinical hypothyroidism

The aim of the present study was to determine whether integrated backscatter (IBS) analysis combined with conventional ultrasonography could differentiate the tissue characteristics of carotid artery intimal hyperplasia in patients with subclinical hypothyroidism (SH). Forty-one patients with SH, as judged by elevated serum TSH levels and free thyroid hormones within the normal range, and 31 sex- and age-matched euthyroid volunteers underwent two-dimensional conventional ultrasonography and IBS analysis of the carotid wall. Carotid intima-media thickness (IMT) and corrected IBS (C-IBS), an index of arterial wall degeneration and fibrosis, were evaluated. Mean IMT as well C-IBS values were higher in SH than in controls (P < 0.0001 for both), whereas the carotid diameter was not significantly different between the two groups. The distribution of C-IBS values in each group showed that regions with higher C-IBS values were found more frequently in SH patients than in control subjects. The percentage of regions that could be considered as fibromatous (C-IBS value from -18 to -21 dB) was 28% in SH and 9% in euthyroid subjects (P < 0.0001). In the SH group, C-IBS values were significantly and positively associated with plasma TSH (r = 0.32, P < 0.05 and r = 0.59, P < 0.0001, respectively) and with both total cholesterol (r = 0.46, P = 0.01) and low density lipoprotein (LDL)-cholesterol (r = 0.55, P = 0.001). Carotid IMT in subclinically hypothyroid patients is higher than that in euthyroid controls. This is characterized by increased IBS values, which are related to the collagen content of the arterial wall. The severity of this remodelling process seems to be related to TSH and cholesterol levels.