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Introduction : To determine age and sex-specific thyrotropin (TSH) and free thyroxine (FT4) reference ranges according to body mass index (BMI) categories. Methods : With regards to the National Academy of Clinical Biochemistry (NACB) criteria, a total of 2818 individuals from the Tehran Thyroid Study population was selected and categorized in three BMI groups. Results : TSH levels did not differ significantly between BMI groups ( p = .054). Females had statistically higher TSH levels than males in all BMI categories ( p < .001). According to age-specific analyses, the youngest category (20-29 years) had the highest median values of serum TSH in all BMI groups. With increasing BMI, the 2.5 th percentile of TSH remained approximately unchanged and the 97.5 th percentile showed an increasing pattern. FT4 level was significantly higher in the normal weight group compared to obese individuals ( p < .001); females had significantly lower FT4 levels than males in normal weight and obese groups ( p < .001). According to age categories, the youngest group (20-29 years) had higher levels of FT4 than the elderly group in all BMI categories. A decreasing pattern in both 2.5 th and 97.5 th percentiles of FT4 was observed along with increasing BMI. Conclusions : Compared to the normal weight population, obese individuals have slightly lower FT4 concentrations accompanied by similar TSH levels. With increasing BMI, upper limits of TSH and FT4 show increasing and decreasing patterns, respectively.

Longitudinal studies considering associations between thyroid function in the reference range (RR) with blood pressure (BP) are scarce and contradictory. We aimed to investigate the associations of serum thyrotropin (TSH) and free T4 (FT4) with different components of BP also incident prehyperetension (preHTN) and HTN during a 9-year follow-up. A sum of 2282 euthyroid individuals from an ongoing population-based cohort study were selected. A sex-stratified multivariate generalized estimating equation (GEE) method was employed. Moreover, a multivariate transitional model was used considering preceding BP status as a predictor of dichotomous outcomes of preHTN and HTN. Multivariate-adjusted GEE analysis revealed a decreasing trend for systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP) and pulse pressure (PP) throughout the study period in both men and women, either adjusted for serum TSH or FT4 levels. Serum FT4 within the RR was positively associated with all BP parameters in total population and in men, but serum TSH had a statistically significant mild increasing effect only on SBP, DBP and MAP of men. Multivariate transitional model found no association between serum TSH levels within the reference range (RR) and BP status; regarding serum FT4, a 1 ng/dl higher FT4 was associated with 40% increased risk of preHTN [OR (95% CI), 1.40 (1.02-1.90)], but not with HTN [OR (95% CI), 0.93 (0.80-1.09)]. It is concluded that serum FT4 within the RR is more strongly associated with BP parameters compared to TSH. This association is not consistent between men and women. Moreover, higher FT4 is associated with increased risk of preHTN., Competing Interests: The authors declare that they have no conflict of interest., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objectives: Previous studies have shown interindividual variation in free thyroxine (FT4) serum levels and thyroid stimulating hormone (TSH) in healthy persons. Genetic factors mainly determine this variation, and genome-wide association studies have increased the number of thyroid function-associated variants. The present study investigates the association of candidate variants with FT4 and TSH in a euthyroid Iranian population. Method: A total of 2931 unrelated euthyroid subjects (FT4 10.29–21.88 pmol/L; TSH 0.32–10 mIU/L, thyroid peroxidase antibody TPOAb < 33 IU/mL in men and < 35 IU/mL in women), with available genotypes were chosen from the Tehran Thyroid Study (TTS), to examine the impact of selected SNPs on thyroid hormone under the additive genetic model. In order to evaluate regional associations with FT4 and TSH levels, a haplotype analysis was done. Results: We identified a strong association between the rs4338740-C allele and TSH in the adjusted model (β = -0.095, P-value = 0.0004). Also, findings indicated that rs4954192 ACMSD and rs4445669 CADM1 correlated with normal TSH levels (P-value = 0.011, P-value = 0.014, respectively). Haplotype analysis revealed that two haplotypes were significantly associated with TSH levels in euthyroid individuals. The ACGA and AC haplotypes on chromosomes 8 and 14 were significantly correlated with normal TSH levels, respectively (P-value = 0.014, P-value = 0.016). Conclusions: This is the first genetic association study with TSH and FT4 reference values in an Iranian population. Our findings indicate that a few gene variants associated with the reference values of TSH in other populations are also associated with the reference values of TSH in Iranians. [ABSTRACT FROM AUTHOR]

Background: Understanding pharmacokinetics (PK) and pharmacodynamics (PD) of the sustained-release liothyronine (SR-T3) is of paramount importance to design therapeutic regimens that are able to simulate normal thyroid hormone secretion while avoiding excursions in the T3 serum concentration. Here, we designed a parallel randomized clinical trial to characterize the PK and PD of the combined preparations of LT4 + SR-T3 in hypothyroid patients. Methods: Radioiodine-treated hypothyroid patients over 20 years of age, who attained euthyroidism with LT4 monotherapy were recruited from the Endocrine Clinic in Tehran. The patients were allocated to two intervention groups of group A: 9 µg SR-T3 plus 68.5 μg LT4 (ratio 1:7.5) and group B: 12 µg SR-T3 plus 60 µg LT4 (ratio 1:5), and a control group with LT4 monotherapy. For PD study, thyroid hormone profile was evaluated at 8 and 12 weeks intervals after intervention. To assess PK properties of SR-T3, T3-Cmax, T3-Tmax and AUC0 − 24 were calculated at the last visit. Results: Serum T4 and FT4 concentrations decreased in the intervention groups after 3 months. No significant difference was observed in serum T3 and FT3 concentrations before and after intervention. Serum T3/T4 ratio increased significantly in the intervention groups after intervention, with the highest increase in group B from 8.6 ± 2.03 at baseline to 12.2 ± 1.6. Comparison of trial groups at follow-up showed no differences in serum TSH, T4, T3 and T3/T4 concentrations among different groups. During 24 h, minimal variation in serum T3 concentration was observed in group B with mean ∆T3 of 15.4 ± 10.5 ng/dl. T3-Tmax, T3-Cmax and AUC0 − 24 in the combined sustained-release preparation were 4.38 ± 1.1 h., 101.0 ± 5.7 ng/dl and 2257 ± 110 ng.h/L, respectively which were significantly different from the control group. Conclusion: Combined treatment with a single dose of SR-T3 plus LT4 is associated with increased serum T3/T4 ratio and minimal excursions in serum T3 concentration during 24 h; however, it was not significantly different from the control group. To incorporate sustained-release T3 in the management of hypothyroidism, a higher ratio of SR-T3 to LT4 than that of the previously recommended by the international organizations is suggested. IRCT registration number: IRCT20100922004794N13. https://www.irct.ir/search/result?query=IRCT20100922004794N13. Registration date: 08/12/2021. [ABSTRACT FROM AUTHOR]

Background: This study compared the degree of sustained control of hyperthyroidism in patients with toxic multinodular goiter (TMNG) treated with long-term methimazole (LT-MMI) or radioactive iodine (RAI). Methods: In this clinical trial, 130 untreated patients with TMNG were randomized to either LT-MMI or RAI treatment. Both groups were followed for 108 to 148 months, with median follow-up durations of 120 and 132 months in the LT-MMI and RAI groups, respectively. Both groups of patients were followed every 1 to 3 months in the first year and every 6 months thereafter. Results: After excluding patients in whom the treatment modality was changed and those who were lost to follow-up, 53 patients in the LT-MMI group and 54 in the RAI group completed the study. At the end of the study period, 50 (96%) and 25 (46%) patients were euthyroid, and two (4%) and 25 (46%) were hypothyroid in LT-MMI and RAI groups, respectively. In the RAI group, four (8%) patients had subclinical hyperthyroidism. The mean time to euthyroidism was 4.3±1.3 months in LT-MMI patients and 16.3± 15.0 months in RAI recipients (P<0.001). Patients treated with LT-MMI spent 95.8%±5.9% of the 12-year study period in a euthyroid state, whereas this proportion was 72.4%±14.8% in the RAI-treated patients (P<0.001). No major treatment-related adverse events were observed in either group. Conclusion: In patients with TMNG, LT-MMI therapy is superior to RAI treatment, as shown by the earlier achievement of euthyroidism and the longer duration of sustained normal serum thyrotropin. [ABSTRACT FROM AUTHOR]

We aimed to assess if changes in thyrotropin (TSH) and free thyroxine (FT4) over 10 years of follow-up would be associated with changes in body mass index (BMI) and waist circumference (WC) or risk of obesity. We enrolled 2317 out of 4179 participants in Tehran Thyroid Study with serum TSH between 0.1–10 mU/l and without history of thyroid medication or surgery. Serum concentrations of FT4 and TSH were measured at baseline and three follow-ups (1999–2011). To account for within-subject correlation, the generalized estimating equation was used to assess the association between one standard deviation(SD) change in the main exposures [cumulative excess (CE)TSH and CEFT4] and changes in BMI and WC; calculated scores of CETSH and CEFT4 were included in models as time-varying exposures. Cumulative excess of TSH or FT4 was not associated with increased incidence of general or abdominal obesity. However, CEFT4 was negatively associated with BMI only in overweight and obese subjects. In GEE analysis, one unit increase in TSH was associated with 0.02 kg/m2 increase in BMI (95% CI: 0.01, 0.03), which remained significant only in women; although the association was not significant after adding FT4 to model. One unit increase in FT4 was associated with 1.5 kg/m2 decrease in BMI (95% CI:−1.8,−1.2) and 4.1 cm decrease in WC (95% CI:−5.1,−3.1) in both sexes independent of TSH and other confounders. Cumulative excess of TSH or FT4 indicated no risk for general or abdominal obesity. However, FT4 was negatively associated with BMI and WC independent of TSH. [ABSTRACT FROM AUTHOR]

Background: Long-term antithyroid drug therapy has become one of the options for treatment of Graves' hyperthyroidism. The aim of this study was to compare thyroid status in those who discontinued methimazole (MMI) treatment after 12.8 years with those who continued MMI as long as 24 years. Methods: Fifty nine patients with Graves' disease on long-term MMI for 14.2 ± 2.9 years were recruited; 32 patients (54%) decided to discontinue MMI and 27 (46%) preferred additional years of MMI treatment. All patients were followed for a mean of 6 additional years. Results: Of 27 patients who continued MMI up to 24 years, suppressed serum thyrotropin (TSH) was not observed in any patient after the seventh year of treatment. Serum free thyroxine, triiodothyronine, TSH and TSH receptor antibody concentrations remained normal up to the length of the study. Mean daily dose of MMI to maintain TSH in the reference range decreased gradually and reached to 2.8 ± 1.7 mg by 24 years of MMI treatment. No adverse reaction related to MMI occured during additional years of therapy. In 32 patients who discontinued MMI, hyperthyroidism relapsed in 6 patients (19%), one left follow-up and 25 (78%) remained euthyroid during the study. Conclusions: Long-term low dose MMI treatment may be a lifelong effective and safe therapeutic modality in patients with Graves' hyperthyroidism for prevention of relapse, if studies from other centers confirm findings of this research. Trial registration: IRCT201009224794N1, 2010-10-25. Retrospectively registered. https://www.irct.ir/trial/5143. [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/Aims: We aimed to evaluate the association between change in thyroid function tests within the euthyroid range and body mass index (BMI) in persons with normal weight at baseline. Methods: This study investigated 1,100 normal-weight euthyroid persons in a population-based cohort study, Tehran Thyroid Study. BMI was calculated and serum concentrations of thyrotropin (TSH) and free T4 (FT4) were assayed at baseline and after 10 years of follow-up. We evaluated the relationship between thyroid and obesity based on 2 definitions for outcome: (1) a binary outcome as BMI <25 or ≥ 25 kg/m2, and (2) a multinomial outcome as normal BMI, overweight, and obese. Results: A total of 569 women and 531 men, aged 36.3 ± 13.5 years, were included. Modified Poisson regression analysis for binary outcome, after adjustment for age, sex, smoking, and antithyroid peroxidase antibody status, revealed a negative association between delta serum FT4 and follow-up BMI (relative risk 0.55 [95% CI 0.37–0.80]) without any significant association between change in serum TSH and follow-up BMI. However, in multinomial logistic regression analysis, we found no relationship between delta serum FT4 or TSH and follow-up BMI categories, for either overweight or obese vs. normal-weight participants. Conclusions: In normal-weight euthyroid individuals, changes in serum concentrations of FT4, but not TSH, may contribute to change in body weight. [ABSTRACT FROM AUTHOR]