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Concept: Thyroid hormone

200

Women have elevated rates of thyroid disease compared to men. Environmental toxicants have been implicated as contributors to this dimorphism, including polybrominated diphenyl ethers (PBDEs), flame retardant chemicals that disrupt thyroid hormone action. PBDEs have also been implicated in the disruption of estrogenic activity, and estrogen levels regulate thyroid hormones. Post-menopausal women may therefore be particularly vulnerable to PBDE induced thyroid effects, given low estrogen reserves. The objective of this study was to test for an association between serum PBDE concentrations and thyroid disease in women from the United States (U.S.), stratified by menopause status.

Concepts: Hormone replacement therapy, Hormone, Menopause, Estrogen, Luteinizing hormone, Thyroid hormone, Flame retardant, Flame retardants

170

C.RF-Tshr(hyt/hyt) mice have a mutated thyroid stimulating hormone receptor (P556L-TSHR) and these mice develop severe hypothyroidism. We found that C.RF-Tshr(hyt/wild) heterozygous mice are also in a hypothyroid state. Thyroid glands from C.RF-Tshr(hyt/wild) mice are smaller than those from wild-type mice, and (125)I uptake activities of the former are significantly lower than those in the latter. When TSHR (TSHR(W)) and P556L-TSHR (TSHR(M)) cDNAs were cloned and co-transfected into HEK 293 cells, the cells retained (125)I-TSH binding activity, but cAMP response to TSH was decreased to about 20% of HEK 293 cells transfected with TSHR(W) cDNA. When TSHR(W) and TSHR(M) were tagged with eCFP or eYFP, we observed fluorescence resonance energy transfer (FRET) in HEK 293 cells expressing TSHR(W)-eCFP and TSHR(W)-eYFP in the absence of TSH, but not in the presence of TSH. In contrast, we obtained FRET in HEK 293 cells expressing TSHR(W)-eCFP and TSHR (M)-eYFP, regardless of the presence or absence of TSH. These results suggest that P556L TSHR has a dominant negative effect on TSHR(W) by impairing polymer to monomer dissociation, which decreases TSH responsiveness and induces hypothyroidism in C.RF-Tshr(hyt/wild) mice.

Concepts: DNA, Thyroid-stimulating hormone, Hypothyroidism, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid hormone, Förster resonance energy transfer, HEK cell

169

Thyroid hormone is essential for normal metabolism and development, and overt abnormalities in thyroid function lead to common endocrine disorders affecting approximately 10% of individuals over their life span. In addition, even mild alterations in thyroid function are associated with weight changes, atrial fibrillation, osteoporosis, and psychiatric disorders. To identify novel variants underlying thyroid function, we performed a large meta-analysis of genome-wide association studies for serum levels of the highly heritable thyroid function markers TSH and FT4, in up to 26,420 and 17,520 euthyroid subjects, respectively. Here we report 26 independent associations, including several novel loci for TSH (PDE10A, VEGFA, IGFBP5, NFIA, SOX9, PRDM11, FGF7, INSR, ABO, MIR1179, NRG1, MBIP, ITPK1, SASH1, GLIS3) and FT4 (LHX3, FOXE1, AADAT, NETO1/FBXO15, LPCAT2/CAPNS2). Notably, only limited overlap was detected between TSH and FT4 associated signals, in spite of the feedback regulation of their circulating levels by the hypothalamic-pituitary-thyroid axis. Five of the reported loci (PDE8B, PDE10A, MAF/LOC440389, NETO1/FBXO15, and LPCAT2/CAPNS2) show strong gender-specific differences, which offer clues for the known sexual dimorphism in thyroid function and related pathologies. Importantly, the TSH-associated loci contribute not only to variation within the normal range, but also to TSH values outside the reference range, suggesting that they may be involved in thyroid dysfunction. Overall, our findings explain, respectively, 5.64% and 2.30% of total TSH and FT4 trait variance, and they improve the current knowledge of the regulation of hypothalamic-pituitary-thyroid axis function and the consequences of genetic variation for hypo- or hyperthyroidism.

Concepts: Genetics, Atrial fibrillation, Hypothyroidism, Hyperthyroidism, Thyroid, Thyroid hormone, Endocrine system, Triiodothyronine

168

Congenital hypothyroidism, usually of the primary and permanent variety, is an eminently preventable cause of growth retardation and mental handicap whose outlook has been transformed by newborn screening, usually involving the measurement of capillary TSH. Severe primary congenital hypothyroidism, due for example to athyreosis, may result in subtle cognitive, behavioural and sensori-motor deficits, but the extent to which these can be offset by optimal postnatal diagnosis and management remains uncertain. This is because the available adult follow-up data reflect the outcome of previous management in the 1970’s and 1980’s, and also because the accurate neuro-psychological assessment of children is difficult, particularly in the preschool population. There is an urgent need to develop new consensus guidelines and to ensure that the children managed according to such guidelines are systematically and prospectively assessed so that good quality outcome data become available. In this review, key recommendations in the management of congenital hypothyroidism include: screening at day 3 so that severely affected infants can begin treatment within the first 10 days of life; setting the thyrotropin (TSH) referral cut-off at 8-10 mU/L; adopting a disciplined diagnostic algorithm to evaluate referred cases, with measurement of venous free thyroxine (T4), TSH and thyroglobulin combined with dual ultrasound and radioisotope imaging; initial treatment with a T4 dose of 50 μg daily in infants weighing ≥ 2.5 kg and 15 μg/kg/day in infants weighing < 2.5 kg followed by weekly review until thyroid function is normalised; and maintenance of free T4 levels between 15-26 pmol/L and TSH between 0.5-5 mU/L thereafter to avoid both under- and overtreatment.

Concepts: Thyroid-stimulating hormone, Hypothyroidism, Hashimoto's thyroiditis, Thyroid, Thyroid hormone, Thyroxine, Newborn screening, Congenital hypothyroidism

167

Thyroid hormone receptor alpha 1 (TRα1) is well recognized for its importance in brain development. However, due to the difficulties in predicting thyroid hormone response elements (TREs) in silico and the lack of suitable antibodies against TRα1 for chromatin immunoprecipitation, only a few direct TRα1 target genes have been identified in the brain. Here we demonstrate that mice expressing a TRα1-GFP fusion protein from the endogenous TRα locus provide a valuable animal model to identify TRα1 target genes. To this end, we analyzed DNA-TRα1 interactions in vivo using chromatin immunoprecipitation with an anti-GFP antibody. We validated our system using established TREs from neurogranin and hairless, and by verifying additional TREs from known TRα1 target genes in brain and heart. Moreover, our model system enabled the identification of novel TRα1 target genes such as RNF166. Our results demonstrate that transgenic mice expressing a tagged nuclear receptor constitute a feasible approach to study receptor-DNA interactions in vivo, circumventing the need for specific antibodies. Models like the TRα1-GFP mice may thus pave the way for genome-wide mapping of nuclear receptor binding sites, and advance the identification of novel target genes in vivo.

Concepts: Antibody, DNA, Protein, Gene expression, Hormone, Receptor, Thyroid hormone, Nuclear receptor

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Background The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition. Methods We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 μg daily, or 25 μg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points). Results The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 μg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], -2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, -2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest. Conclusions Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST ClinicalTrials.gov number, NCT01660126 .).

Concepts: Clinical trial, Thyroid-stimulating hormone, Hypothyroidism, Hashimoto's thyroiditis, Hyperthyroidism, Thyroid, Thyroid hormone, Placebo

83

 To estimate the effectiveness and safety of thyroid hormone treatment among pregnant women with subclinical hypothyroidism.

Concepts: Childbirth, Prolactin, Thyroid disease, Constipation, Hypothyroidism, Hyperthyroidism, Thyroid, Thyroid hormone

30

The primary function of the thyroid gland is to metabolize iodide by synthesizing thyroid hormones, which are critical regulators of growth, development and metabolism in almost all tissues. So far, research on thyroid morphogenesis has been missing an efficient stem-cell model system that allows for the in vitro recapitulation of the molecular and morphogenic events regulating thyroid follicular-cell differentiation and subsequent assembly into functional thyroid follicles. Here we report that a transient overexpression of the transcription factors NKX2-1 and PAX8 is sufficient to direct mouse embryonic stem-cell differentiation into thyroid follicular cells that organize into three-dimensional follicular structures when treated with thyrotropin. These in vitro-derived follicles showed appreciable iodide organification activity. Importantly, when grafted in vivo into athyroid mice, these follicles rescued thyroid hormone plasma levels and promoted subsequent symptomatic recovery. Thus, mouse embryonic stem cells can be induced to differentiate into thyroid follicular cells in vitro and generate functional thyroid tissue.

Concepts: Gene expression, Developmental biology, Stem cell, Hormone, Cellular differentiation, Embryonic stem cell, Thyroid, Thyroid hormone

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Filial imprinting in precocial birds is the process of forming a social attachment during a sensitive or critical period, restricted to the first few days after hatching. Imprinting is considered to be part of early learning to aid the survival of juveniles by securing maternal care. Here we show that the thyroid hormone 3,5,3'-triiodothyronine (T(3)) determines the start of the sensitive period. Imprinting training in chicks causes rapid inflow of T(3), converted from circulating plasma thyroxine by Dio2, type 2 iodothyronine deiodinase, in brain vascular endothelial cells. The T(3) thus initiates and extends the sensitive period to last more than 1 week via non-genomic mechanisms and primes subsequent learning. Even in non-imprinted chicks whose sensitive period has ended, exogenous T(3) enables imprinting. Our findings indicate that T(3) determines the start of the sensitive period for imprinting and has a critical role in later learning.

Concepts: Endothelium, Thyroid, Thyroid hormone, Learning, Developmental psychology, Ethology, Critical period, Imprinting

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AIMS: Understanding the exact relationship between serum thyrotropin/thyroid stimulating hormone (TSH) and free thyroxine (FT(4)) is a prerequisite for improving diagnostic reliability and clinical decision making. METHODS: We (1) retrospectively studied the relationship between TSH and FT(4) in a large unselected clinical sample (n=6641) of primary hypothyroid, euthyroid and hyperthyroid subjects, and (2) applied a mathematical model of thyroid hormone feedback control to assess the relation between structural parameters and TSH levels in the different functional states. RESULTS: When separately analysing total sample and untreated subjects, the correlation slope for logTSH versus FT(4) for hypothyroid subjects was significantly different from that of the euthyroid panel and hyperthyroid subjects (the latter being compromised by reaching the TSH assay’s lower detection limit). As trends between functional states changed, each functional segment appeared to become differently regulated. Theoretical modelling and sensitivity analysis revealed that the influence of various structural parameters on TSH levels also depends on the overall function of the feedback loop. CONCLUSIONS: Our data suggest that the states of hypothyroidism, euthyroidism and hyperthyroidism can be regarded as differently regulated entities. The apparent complexity could be replicated by mathematical modelling suggesting a hierarchical type of feedback regulation involving patterns of operative mechanisms unique to each condition. For clinical purposes and assay evaluation, neither the standard model relating logTSH with FT(4), nor an alternative model based on non-competitive inhibition can be reliably represented by a single correlation comparing all samples for both hormones in one all-inclusive group.

Concepts: Physics, Thyroid-stimulating hormone, Thyroid disease, Hypothyroidism, Hyperthyroidism, Thyroid, Thyroid hormone, Triiodothyronine