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Background: Accurate assessment of thyroid status during pregnancy is vital for maternal and fetal health. Because free thyroxine (FT4) values in pregnancy vary widely between methods, assessment of total T4 (TT4) and FT4 index (FT4I) may be superior to FT4 in pregnant women. However, trimester-specific reference intervals for FT4I have not yet been established. In this longitudinal self-sequential survey, we aimed at determining the trimester-specific reference range for FT4I in healthy Iranian women with singleton pregnancies. Methods: A total of 466 healthy pregnant women were evaluated. After exclusion of women with history, ultrasonographic, or laboratory evidence of any thyroid disorder or iodine deficiency and those who were positive for thyroid autoantibodies, 152 women entered the study. Serum thyrotropin (TSH), TT4, and triiodothyronine-resine uptake were measured by an immunoassay method. Reference intervals were defined as 5th and 95th percentiles, using the bootstrap-based procedure. Results: Mean values in the first, second, and third trimesters were 1.7±1.5, 1.9±1.8, and 1.9±1.8 mIU/L for TSH; 12.9±3, 14.4±3.1, and 13.6±3.3 μg/dL for TT4; and 12.8±3.5, 14.2±3.3, and 13.5±3.8 for FT4I, respectively. Reference intervals in the first, second, and third trimesters were as follows (respectively): TSH-0.2-3.9, 0.5-4.1, and 0.6-4.1 mIU/L; TT4-8.2-18.5, 10.1-20.6, and 9-19.4 μg/dL; and FT4I-8.5-19, 9.7-21, and 8.7-20.4. Serum TSH had no significant correlation with TT4. Serum TSH had a significant but weak correlation with FT4I only in the first trimester ( r=−0.24, p=0.006). Conclusion: This study, for the first time, establishes the trimester-specific reference intervals for FT4I in a reference population of normal iodine-sufficient pregnant Iranian women. [ABSTRACT FROM AUTHOR]

Background: This study aimed to compare the effectiveness and safety of radioiodine (RAI) and long-term methimazole (MMI) in the treatment of subclinical hyperthyroidism (SH) in the elderly. Methods: From 306 patients, aged ≥65 years, with SH, 83 patients with thyrotropin <0.1 mU/L entered the study. In this randomized parallel-group trial, 41 and 42 patients were randomized to either RAI or long-term MMI treatment, respectively. Results: In the RAI and MMI groups, 3 and 4 patients were excluded due to side effects, choosing other modes of treatment, and not returning for follow-up; 35 and 36 patients completed 60 months of follow-up, respectively. In the RAI group, 23 (66%) became hypothyroid, and 12 (34%) remained euthyroid 60 months after a fixed dose of 15 mCi RAI. In the MMI group, the starting dose was 10 mg daily and decreased to 4.9 ± 1.0, 4.3 ± 1.0, 4.4 ± 1.4, 4.3 ± 1.8, and 3.7 ± 1.3 mg after 1, 2, 3, 4, and 5 years of continuous MMI treatment, employing titration method. By the end of study, 34 (94%) patients were euthyroid and 2 patients with diffuse goiter developed spontaneous hypothyroidism with MMI treatment. Minor adverse events occurred in both groups in the first four months of treatment. No death or serious side effects were observed during 60 months of follow-up. Conclusions: Both RAI and long-term low-dose MMI therapies are effective and safe for treatment of SH in the elderly. [ABSTRACT FROM AUTHOR]

Introduction: Autoimmune thyroid disease is the most common autoimmune disorder. Evidence regarding causes of the high prevalence and incidence of thyroid autoimmunity in women, and especially women of reproductive age, is still inconclusive and previous studies have suggested genetic, environmental, and existential factors to play a role in its pathogenesis. In this study, we aimed to investigate the effect of parity and other reproductive factors on the incidence of thyroid autoimmunity within the framework of the Tehran Thyroid Study (TTS). Materials and Methods: This study was conducted within the framework of the TTS and 1999 nonpregnant euthyroid thyroid peroxidase antibody (TPOAb) negative women were followed up for an average of 8.3 years. A pooled logistic regression model was used to assess the association (odds ratio) between time-dependent covariates parity, menopause, and abortion, and incidence of TPOAb positivity. Results: The total incidence rate of TPOAb positivity was 8.65 [7.35–10.18] per 1000 person-years. We found no significant association between changes in the number of parity and risk of developing TPOAb using multiple pooled logistic models both as crude effect and after adjustment for age, body mass index, and smoking. Similarly, there was no association between changes of parity, menopause, and abortion status, and incidence of TPOAb positivity. Conclusions: Parity does not seem to have an independent role in triggering thyroid autoimmunity, but vast immunological and physiological changes during pregnancy may act as a precipitating factor in the context of other genetic and environmental modifiers. [ABSTRACT FROM AUTHOR]

Background: Thyroid disorders such as subclinical hypothyroidism and isolated maternal hypothyroxinemia are understudied in pregnant women, despite their possible adverse effects on the health of mother and child. Also, the role of iodine deficiency in developing such disorders has not yet been fully understood. Methods: The present national population-based cross-sectional study was conducted on 1080 randomly recruited pregnant women, aged 20–40 from 12 provinces of Iran from 2013 to 2014. Serum concentrations of thyrotropin, T4, thyroid peroxidase antibody (TPOAb), and triiodothyronine (T3) resin uptake values were measured in fasting blood samples, and urinary iodine concentration (UIC) was measured in three separate urine samples. Multinomial logistic regression was run to analyze the possible risk factors regarding thyroid disorders. To clarify the role of iodine in thyroid status specifically, the determinants of UIC and its correlations with thyroid function tests were investigated independently and through subgroup analysis. Results: Isolated hypothyroxinemia was the most common thyroid disorder (9.9%), followed by subclinical hypothyroidism (8%). In comparison to euthyroid pregnant women, isolated hypothyroxinemia was more likely in pregnant women older than 30 years (odds ratio [OR] = 1.6), in the second and the third trimesters (OR = 2.62 and 2.12 respectively), with history of multiparity (OR = 1.72), residing in rural areas (OR = 1.57) and in the capital province of the country (OR = 3.3). Subclinical hypothyroidism was more likely in TPOAb positive pregnant women (OR = 2.56). All the mentioned ORs were statistically significant (p < 0.05). The UIC did not correlate significantly with any of the thyroid function tests in the study population. Subgroup analysis showed a significant correlation between UIC and T4 in pregnant women with subclinical hypothyroidism (p < 0.05). Conclusion: Isolated maternal hypothyroxinemia was the most prevalent thyroid disorder in Iranian pregnant women and its associated risk factors were identified. Although the calculated prevalence of thyroid disorders was expected in a moderately iodine deficient setting, no correlations between UICs and thyroid function tests were found at the individual level. The contribution of iodine deficiency to thyroid condition for each pregnant woman may be more evident in pregnant women with certain thyroid disorders or those with long-term iodine deficiency. [ABSTRACT FROM AUTHOR]

Background: Studies differ regarding whether, compared with courses of conventional duration, longer-term antithyroid drug treatment increases frequency of remission in patients with Graves' hyperthyroidism. We prospectively conducted a randomized, parallel-group study comparing relapse rates in patients receiving longer-term versus conventional-length methimazole therapy. We also sought variables associated with relapse following the latter. Methods: We enrolled 302 consecutive patients with untreated first episodes of Graves' hyperthyroidism. After 18–24 months of methimazole, 258 patients (85.4%) were randomized to an additional 36–102-month courses ("long-term group": n = 130; scheduled total time on methimazole: 60–120 months) or discontinuation of methimazole ("conventional group": n = 128). Patients were followed 48 months postmethimazole cessation. We performed Cox proportional hazards modeling to identify factors associated with relapse after conventional courses. Results: Methimazole was given for 95 ± 22 months in long-term patients and 19 ± 3 months in the conventional group. Fourteen patients experienced cutaneous reactions and 2 liver enzyme elevations during the first 18 months of treatment; no further methimazole-related reactions were observed despite therapy for up to another 118 months. Hyperthyroidism recurred within 48 months postmethimazole withdrawal in 15% (18/119) of long-term patients versus 53% (65/123) of conventional group patients. In the conventional group, older age, higher triiodothyronine or thyrotropin receptor antibody concentrations, lower thyrotropin concentration, or possession of the rs1879877 CD28 polymorphism or the DQB1-05 HLA polymorphism were independently associated with relapse. Conclusion: Administration of low-dose methimazole for a total of 60–120 months safely and effectively treats Graves' hyperthyroidism, with much higher remission rates than those attained by using conventional 18–24-month courses. [ABSTRACT FROM AUTHOR]

Background: This study aimed to compare the effectiveness and safety of long-term methimazole (MMI) and radioiodine (RAI) in the treatment of toxic multinodular goiter (TMNG). Methods: In this randomized, parallel-group trial, 130 consecutive and untreated patients with TMNG, aged <60 years, were enrolled and randomized to either long-term MMI or RAI treatment. Both groups of patients were followed for 60–100 months, with median durations of 72 and 84 months in the MMI and RAI groups, respectively. Results: In the MMI and RAI groups, 12 and 11 patients, respectively, were excluded because of side effects, choosing other modes of treatment and not returning for follow-up; 53 and 54 patients, respectively, completed the study for 60–100 months. In the MMI group, two patients (3.8%) experienced subclinical hypothyroidism, and 51 (96.2%) remained euthyroid until the end of study. The dosage of MMI to maintain euthyroidism was 6.3 ± 2.0, 4.5 ± 0.9, and 4.1 ± 1.0 mg daily during the first, third, and fifth years of continuous MMI treatment. One patient had elevated liver enzymes, and three developed skin reactions during the first three months, but no adverse effects from MMI occurred from 4 to 100 months of therapy. In the RAI group, 22 (41%) became hypothyroid, 12 (22%) had persistence or recurrence of hyperthyroidism, and 20 (37%) became euthyroid after 16.7 ± 2.7 mCi 131I. Conclusion: Long-term, low-dose MMI treatment for 60–100 months is a safe and effective method for treatment of TMNG, and is not inferior to RAI treatment. [ABSTRACT FROM AUTHOR]

Background: Considering inconsistent and conflicting data on associations of thyroid function, within the reference range, with anthropometric measures and metabolic syndrome, this study aimed to investigate the relationship between thyroid function and different obesity phenotypes over nine years of follow-up. Methods: This study was conducted on 1938 individuals from an ongoing population-based cohort study, the Tehran Thyroid Study. Participants were categorized into four obesity phenotypes based on body mass index and metabolic status. To investigate the associations of thyrotropin and free thyroxine (fT4) with incidence of different obesity phenotypes across the study period, a multivariate approach based on a generalized estimating equation method was used. Results: At baseline, individuals with the metabolically healthy normal weight (MHNW) phenotype had higher serum fT4 levels (1.2 ± 0.16 ng/dL vs. 1.14 ± 0.14 ng/dL, 1.16 ± 0.14 ng/dL, and 1.17 ± 0.15 ng/dL in metabolically healthy obese [MHO], metabolically unhealthy normal weight, and metabolically unhealthy obese individuals, respectively). The results of the generalized estimating equation analysis after multivariate adjustment for age, sex, smoking, physical activity, education level, thyroid peroxidase antibody status, and homeostasis model assessment-insulin resistance showed that each 1 ng/dL increment in fT4 levels within the reference range was accompanied with a 1.65-fold [confidence interval (CI) 1.09–2.5] increase of developing the MHNW phenotype during 9.2 years of follow-up. Moreover, each 1.0 ng/dL increment in fT4 within the reference range was associated with a 50% decreased risk of developing the MHO phenotype (odds ratio = 0.50 [CI 0.32–0.76]). Meanwhile, a significant positive association was found between serum thyrotropin levels and development of the metabolically unhealthy normal weight phenotype (odds ratio = 1.22 [CI 1.01–1.48]). Conclusions: Serum fT4 concentrations within the reference range are associated with the development of some obesity phenotypes, including the MHNW and MHO phenotypes, after consideration of potential confounders. [ABSTRACT FROM AUTHOR]

Background: The association of changes in thyroid hormone values over time with the incidence of metabolic syndrome (MetS) has not yet been evaluated. For the first time, this study assessed the effect of thyroid hormone variations in the subclinical and euthyroid range on the incidence of MetS and its components over a 10-year follow-up in an adult population. Methods: Data were analyzed from the prospective population-based Tehran Thyroid Study. Of 5786 randomly selected subjects aged ≥20 years, after excluding subjects with MetS ( n = 1403), those with serum thyrotropin (TSH) >10 or <0.1 mIU/L ( n = 104), those taking thyroid drugs ( n = 85) or corticosteroids ( n = 97), those with a body mass index (BMI) <18.5 kg/m2, those with a glomerular filtration rate <30, and those with a history of cancer (12), data for 2393 subjects were analyzed. Body weight, waist circumference, and blood pressure were measured, and serum concentrations of lipids and lipoproteins, fasting blood glucose, insulin, free thyroxine (fT4), and TSH were assayed at baseline and during three follow-up studies at three-year intervals. MetS was determined using definition of the Joint Interim Statement, adjusted for the Iranian population. Results: An increase in fT4 values overtime was associated with lower odds of abdominal obesity (odds ratio [OR] = 0.49 [confidence interval (CI) 0.35-0.69]) and hypertriglyceridemia (OR = 0.57 [CI 0.41-0.78]), and with higher odds of hypertension (OR = 1.35 [CI 1.05-1.74]), adjusted for age, sex, smoking, BMI, and Homeostasis Model Assessment Index for Insulin Resistance. fT4 was associated with lower odds of MetS in the crude model, and after adjustment for age, sex, and smoking (OR = 0.59 [CI 0.39-0.9]). This association lost its significance after further adjusting for BMI. In a subgroup analysis of obese (i.e. BMI ≥30 kg/m2) and non-obese (i.e., BMI <30 kg/m2) subjects, fT4 was a significant predictor of MetS only in non-obese subjects after adjusting for age, sex, and smoking (β = 0.49 [CI 0.29-0.83], p = 0.007) and also after further adjustment for Homeostasis Model Assessment Index for Insulin Resistance (β = 0.57 [CI 0.34-0.96], p = 0.03). Serum TSH variations over time were not associated with any of the MetS components or with odds of MetS. Conclusion: A decrease in serum fT4 values is associated with an increased risk for MetS, especially in non-obese adults. [ABSTRACT FROM AUTHOR]

Objective: Considering the limited data available on the natural course of euthyroidism, this study was designed to evaluate the progression in time from euthyroidism to subclinical or overt hypo- or hyperthyroidism. Methods: This study was conducted within the framework of the Tehran Thyroid Cohort Study, in which 5783 individuals aged 40.4 ± 0.2 years were followed for six years. The overall loss to follow-up rate was 8.3%. After applying exclusion criteria, data of 4204 euthyroid subjects remained for analysis of a six-year natural course analysis. Thyroid function tests, clinical characteristics, and metabolic characteristics were assessed at baseline and every three years. Results: The annual incidence rates [confidence intervals (CI)] of subclinical and overt hypothyroidism were 7.62 [CI 7.39-7.85) and 2.0 [CI 1.94-2.06] per 1000 persons, respectively. For thyroid hyperfunction, the annual incidence rates of subclinical and overt hyperthyroidism were 0.92 [0.90-0.95) and 0.68 [0.66-0.70) per 1000 persons, respectively. Euthyroid persistency was 93.24% during 6 years. Predictive factors for conversion to thyroid dysfunction were thyrotropin, free thyroxine and thyroid peroxidase antibody levels, sex, and smoking. Criteria for early diagnosis of hypothyroidism (i.e., sensitivity of 94% and specificity of 82%, p < 0.0001) were obtained based on baseline and three-year follow-ups of thyroid function tests and thyroid peroxidase antibody. Early diagnosis of hypothyroidism was significantly associated with impaired glucose tolerance (relative risk with 3.03 [CI 1.36-6.75]; p = 0.007), high cholesterol (relative risk 2.46 [CI 1.45-4.18]; p = 0.001), obesity (relative risk 2.92 [CI 1.64-5.2]; p < 0.001), and hypertension (relative risk 1.68 [CI 1.53-1.84]; p < 0.04). Conclusion: This study shows that after a six-year follow-up in an iodine sufficient area, 6.7% of euthyroid subjects were found to progress to thyroid dysfunction, in particular subclinical hypothyroidism. [ABSTRACT FROM AUTHOR]

Background: Because of their increased need for iodine, pregnant women are among the high-risk groups for iodine deficiency. The purpose of this study was to evaluate the effectiveness of an educational program on the iodine nutrition status of pregnant women. Methods: In this randomized controlled trial, 100 pregnant women were randomly selected from five healthcare centers in the southern region of Tehran, the capital of Iran. In the intervention group, pregnant women received a four-month educational program, which included two face-to-face educational sessions, using a researcher-designed educational pamphlet in the second and third trimesters, and two follow-up telephone calls. Knowledge, attitude, and practice (KAP) scores, urinary iodine concentration (UIC), and salt iodine content were assessed at baseline and four months after the intervention. Results: At baseline, there were significant associations between knowledge and attitude ( r = 0.38, p = 0.03) between practice and UIC ( r = 0.28, p = 0.01) and between UIC and iodine content of salt ( r = 0.24, p = 0.009). Although a significant difference was found in mean KAP scores between the two groups after the educational intervention, scores were significantly higher in the intervention group compared with controls ( p < 0.01). There were no significant differences in UIC and iodine content of salt between the two groups at follow-up. Conclusions: Despite educational intervention increasing KAP among women regarding the importance of iodine and iodized salt consumption during pregnancy, their iodine status did not improve. Considering the main socio-environmental determinants of iodine deficiency, in particular, the monitoring of salt fortification, prescribing iodine containing supplements as well as improving health literacy in pregnant women seem essential strategies. [ABSTRACT FROM AUTHOR]

Background: Current guidelines used for establishing reference intervals for thyroid peroxidase antibodies (TPOAb), recommended by the National Academy of Clinical Biochemistry, have been a matter of controversy. The present study sought to determine TPOAb reference intervals for different age and sex groups, as well as the TPOAb cutoff points for subclinical and overt hypothyroidism in an iodine-sufficient population. Methods: This cross-sectional study was conducted within the framework of the prospective Tehran Thyroid Study (TTS), in which 4174 healthy euthyroid individuals were followed for 10 years. Thyroid function tests and TPOAb were assessed. Results: The mean age ± standard deviation of participants was 39.3 ± 15.2 years. Estimated reference intervals for TPOAb corresponding to the 2.5th and 97.5th percentiles were 1.5-32.8 and 2.1-35 IU/mL in males and females, respectively. There were no significant variations in the different age groups in either sex. The optimal cutoff points for TPOAb were 18.38 and 14.77 IU/mL for predicting clinical and subclinical hypothyroidism, respectively. Conclusions: This study establishes the reference intervals and the optimal cutoff points for TPOAb in an iodine-sufficient population. [ABSTRACT FROM AUTHOR]

Context: The association between thyroid hormones within the euthyroid range and metabolic syndrome is not clear. Aim: This study evaluated the relationship between thyroid hormones and metabolic syndrome and its components in euthyroid subjects. Design and setting: This is a cross-sectional population based study conducted within the framework of the cohort of the Tehran Thyroid Study. Participants: Out of 5786 subjects aged ≥20 years, 3755 euthyroid subjects without a history of thyroid disorders, diabetes, or use of steroids or lipid-lowering agents were investigated. Outcome measures: Body weight, waist circumference (WC), and blood pressure (BP) were measured. Serum concentrations of lipids and lipoproteins, fasting blood glucose (FBG), insulin, free T4 (FT4), and thyrotropin (TSH) were assayed. Metabolic syndrome was determined by definition of the Joint Interim Statement adjusted for the Iranian population. Results: After adjustment for age, sex, and smoking, serum FT4 was significantly associated with high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TGs), WC, systolic BP, and diastolic BP; the associations that remained significant after further adjustment for body mass index (BMI) and the homeostasis model assessment index for insulin resistance (HOMA-IR) except for HDL-C. Serum TSH was associated only with TGs after adjustments for age, sex, smoking, and BMI, an association that disappeared after further adjustment for HOMA-IR. Serum FT4 was negatively associated (β=−0.02, 95% confidence interval [CI: −0.03, −0.01]) and TSH was positively associated (β=0.03 [CI: 0.01, 0.04) with insulin resistance. The prevalence of metabolic syndrome decreased from 30.1% in the lowest FT4 tertile to 22.4% in the highest FT4 tertile ( p<0.001). The prevalence of other metabolic syndrome components decreased significantly from higher to lower FT4 tertiles. Higher FT4 values were associated with lower odds of metabolic syndrome (OR=0.96 [95% CI: 0.92, 0.99]; p=0.01). Conclusion: In euthyroid subjects, FT4, rather than TSH, is associated with risk of metabolic syndrome and its components. [ABSTRACT FROM AUTHOR]

A correction to the article "Establishment of the Trimester-Specific Reference Range for Free Thyroxine Index" that was published in the March 2013 issue of the journal is presented.