scholarly journals Thyroid function and effect of aging in combined hetero/homozygous mice deficient in thyroid hormone receptors alpha and beta genes

2002 ◽  
Vol 172 (1) ◽  
pp. 177-185 ◽  
Author(s):  
RE Weiss ◽  
O Chassande ◽  
EK Koo ◽  
PE Macchia ◽  
K Cua ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Function ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptors ◽  
Thyroid Function Tests ◽  
Wild Type ◽  
Heterozygous Mouse ◽  
Tsh Secretion ◽  
Homozygous Deletions ◽  
Serum Tsh

The maintenance of thyroid hormone (TH) homeostasis is dependent on the synthesis and secretion of TH regulated by TSH. This is achieved, in turn, by the negative feedback of TH on TSH secretion and synthesis, which requires the interaction with TH receptors (TRs). Derived by alternative splicing of two gene transcription products, three TRs (TRbeta1, TRbeta2 and TRalpha1) interact with TH while another, TRalpha2, binds to DNA but not to TH. In this study we compare the results of thyroid function tests in mice with deletions of the TRalpha and TRbeta genes alone and present novel data on mice that are double homozygous and combined heterozygous. Homozygous deletions of both the TRalpha and TRbeta in the same mouse (TRalphao/o; TRbeta-/-) resulted in serum TSH values only slightly lower than those in athyreotic, Pax8 knockout mice. Whereas the absence of TRalpha alone does not cause resistance to TH, the absence of TRbeta in the presence of TRalpha results in a 205, 169, 544% increase in serum thyroxine (T(4)), triiodothyronine (T(3)) and TSH concentrations respectively. However, in the absence of TRbeta, loss of one TRalpha allele can worsen the resistance to TH with a 243 and 307% increase in T(4) and T(3) respectively. Similarly, while the heterozygous mouse with a single TRbeta allele shows no alteration in thyroid function, the concomitant deletion of TRalpha brings about mild but significant resistance to TH. Furthermore, the severity of the resistance to TH was noted to decrease with age in parallel with the decrease in serum free T(4) values also seen in wild-type mice. These results demonstrate that (1) unliganded TRalpha or TRbeta are not absolutely necessary for the upregulation of TSH; (2) TRbeta but not TRalpha is sufficient for TH-mediated downregulation of TSH; and (3) TRalpha may partially substitute for TRbeta in mediating a partial TH-dependent TSH suppression.

scholarly journals Differences between the silencing-related properties of the extreme carboxyl-terminal regions of thyroid hormone receptors alpha 1 and beta 1

2000 ◽  
Vol 167 (2) ◽  
pp. 219-227 ◽  
Author(s):  
K Nishiyama ◽  
A Matsushita ◽  
H Natsume ◽  
T Mikami ◽  
R Genma ◽  
...  
Keyword(s):  
Amino Acid ◽  
Thyroid Hormone ◽  
Hormone Receptors ◽  
Target Genes ◽  
Thyroid Hormone Receptor ◽  
Thyroid Hormone Receptors ◽  
Human Thyroid ◽  
Wild Type ◽  
Amino Acid Deletion ◽  
The Difference

Human thyroid hormone receptor (TR) is encoded by two distinct genes, TR alpha and TR beta. TR heterodimerizes with retinoid X receptor (RXR) and binds efficiently to the thyroid hormone (T(3)) response element (TRE) of target genes. In the absence of T(3), unliganded TR suppresses the basal promoter activity of positively regulated genes (silencing). Silencing mediator for retinoid and thyroid hormone receptors (SMRT) and nuclear receptor co-repressor (N-CoR) interact with unliganded TR and function as corepressor proteins. Previously, we found beta F451X with carboxyl (C)-terminal 11-amino acid deletion had stronger silencing potency than wild-type TR beta 1 and beta E449X with C-terminal 13-amino acid deletion on a subset of TREs. In the present study, to assess the isoform-specific effects of the C-terminal truncations on TR silencing, we constructed two mutant TR alpha 1s (alpha F397X and alpha E395X) with the same respective C-terminal truncations as beta F451X and beta E449X and analysed their silencing activities. Unlike beta F451X and beta E449X, alpha F397X and alpha E395X showed similarly stronger silencing potency than wild-type TR alpha 1. We further studied the abilities of wild-type and the mutant TR beta 1s and alpha 1s on RXR and co-repressor binding by a two-hybrid interference assay. beta F451X had significantly stronger abilities to bind to RXR and SMRT than did wild-type TR beta 1 and beta E449X. In contrast, wild-type TR alpha 1, alpha F397X and alpha E395X showed similar abilities to bind to RXR and SMRT. beta E449X and alpha E395X, which have identical C-terminal truncation, showed less ability to bind to N-CoR than did wild-type TR beta 1 and beta F451X and wild-type TR alpha 1 and alpha F397X respectively. These results indicate that an identical C-terminal truncation gives rise to different effects on TR beta 1 and alpha1 with respect to silencing potency, RXR binding and SMRT binding. The difference in the silencing potency among wild-type TR beta 1, beta F451X and beta E449X correlated well with the difference in the ability to bind co-repressor SMRT.

Effect of diphenylhydantoin on hypothalamic-pituitary-thyroid function in the rat

1980 ◽  
Vol 239 (6) ◽  
pp. E468-E473
Author(s):  
T. Theodoropoulos ◽  
S. L. Fang ◽  
F. Azizi ◽  
S. H. Ingbar ◽  
A. G. Vagenakis ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Function ◽  
Direct Effect ◽  
Large Dose ◽  
Inhibitory Effect ◽  
Thyrotropin Releasing Hormone ◽  
Time Dependent ◽  
Tsh Secretion ◽  
Normal Rat ◽  
Serum Tsh

Chronic diphenylhydantoin (DPH) administration (5 mg x 100 g body wt-1 x day-1) to the normal rat is associated with a decrease in the serum thyroxine (T4) and triiodothyronine (T3) concentrations without an appropriate rise in the serum thyrotropin (TSH) concentration, suggesting a possible direct effect of DPH on TSH secretion. To further study this possibility, DPH was administered chronically to thyroidectomized, hypothyroid rats. In the hypothyroid rats treated chronically with DPH, serum TSH did not increase, pituitary TSH content was significantly decreased, and the serum TSH response to thyrotropin-releasing hormone (TRH) was decreased compared to that of diluent-treated, hypothyroid rats. Hypothalamic TRH content was similar in DPH and diluent-treated rats. These findings suggest that DPH suppresses pituitary TSH secretion, probably as a thyroid hormone agonist. The effect of a single large dose of DPH (20 mg/100 g body wt) administered to thyroidectomized rats also decreased serum tSH but, in contrast to the findings in chronically treated rats, hypothalamic TRH and pituitary TSH content and the serum TSH responses to TRH were increased. These differences may be due to the acute inhibitory effect of a large dose of DPH on hypothalamic TRH release. Furthermore, because the effect of thyroid hormone on regulating pituitary TSH synthesis and release is dose and time dependent, the effect of DPH as a thyroid hormone agonist on pituitary TSH dynamics may also be variable.

scholarly journals Thyroid Function Disturbance and Type 3 Iodothyronine Deiodinase Induction after Myocardial Infarction in Rats—A Time Course Study

Endocrinology ◽  
2007 ◽  
Vol 148 (10) ◽  
pp. 4786-4792 ◽  
Author(s):  
Emerson L. Olivares ◽  
Michelle P. Marassi ◽  
Rodrigo S. Fortunato ◽  
Alba C. M. da Silva ◽  
Ricardo H. Costa-e-Sousa ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Thyroid Hormone ◽  
Thyroid Function ◽  
Time Course ◽  
Thyroid Function Tests ◽  
Iodothyronine Deiodinase ◽  
Serum T4 ◽  
Time Course Study ◽  
Type 3 ◽  
Serum Tsh

In humans, there is a significant decrease in serum T3 and increase in rT3 at different time points after myocardial infarction, whereas serum TSH and T4 remain unaltered. We report here a time course study of pituitary-thyroid function and thyroid hormone metabolism in rats subjected to myocardial infarction by left coronary ligation (INF). INF- and sham-operated animals were followed by serial deiodination assays and thyroid function tests, just before, and 1, 4, 8, and 12 wk after surgery. At 4 and 12 wk after INF, liver type 1 deiodinase activity was significantly lower, confirming tissue hypothyroidism. Type 3 deiodinase (D3) activity was robustly induced 1 wk after INF only in the infarcted myocardium. Reminiscent of the consumptive hypothyroidism observed in patients with large D3-expressing tumors, this induction of cardiac D3 activity was associated with a decrease in both serum T4 (∼50% decrease) and T3 (37% decrease), despite compensatory stimulation of the thyroid. Thyroid stimulation was documented by both hyperthyrotropinemia and radioiodine uptake. Serum TSH increased by 4.3-fold in the first and 3.1-fold in the fourth weeks (P < 0.01), returning to the basal levels thereafter. Thyroid sodium/iodide-symporter function increased 1 wk after INF, accompanying the increased serum TSH. We conclude that the acute decrease in serum T4 and T3 after INF is due to increased thyroid hormone catabolism from ectopic D3 expression in the heart.

scholarly journals Placenta Passage of the Thyroid Hormone Analog DITPA to Male Wild-Type and Mct8-Deficient Mice

Endocrinology ◽  
2014 ◽  
Vol 155 (10) ◽  
pp. 4088-4093 ◽  
Author(s):  
Alfonso Massimiliano Ferrara ◽  
Xiao-Hui Liao ◽  
Pilar Gil-Ibáñez ◽  
Juan Bernal ◽  
Roy E. Weiss ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Monocarboxylate Transporter ◽  
Thyroid Function Tests ◽  
Wild Type ◽  
Peripheral Tissues ◽  
Hormone Analog ◽  
Neurological Phenotype ◽  
Serum T4 ◽  
Mct8 Deficiency ◽  
Serum Tsh

Abstract Monocarboxylate transporter 8 (MCT8) deficiency causes severe X-linked intellectual and neuropsychological impairment associated with abnormal thyroid function tests (TFTs) producing thyroid hormone (TH) deprivation in brain and excess in peripheral tissues. The TH analog diiodothyropropionic acid (DITPA) corrected the TFTs abnormalities and hypermetabolism of MCT8-deficient children but did not improve the neurological phenotype. The latter result was attributed to the late initiation of treatment. Therefore, we gave DITPA to pregnant mice carrying Mct8-deficient embryos to determine whether DITPA, when given prenatally, crosses the placenta and affects the serum TFTs and cerebral cortex of embryos. After depletion of the endogenous TH, Mct8-heterozygous pregnant dams carrying both wild-type (Wt) and Mct8-deficient (Mct8KO) male embryos were given DITPA. Effects were compared with those treated with levothyroxine (L-T4). With DITPA treatment, serum DITPA concentration was not different in the two genotypes, which produced equal effect on serum TSH levels in both groups of pups. In contrast, with L-T4 treatment, TSH did not normalize in Mct8KO pups whereas it did in the Wt littermates and dams despite higher concentration of serum T4. Finally, both treatments similarly modulated the expression of the TH-dependent genes Shh, Klf9, and Aldh1a3 in brain. Thus, the ability of DITPA to cross the placenta, its thyromimetic action on the expression of TH-dependent genes in brain, and its better accessibility to the pituitary than L-T4, as assessed by serum TSH, make DITPA a candidate for the prenatal treatment of MCT8 deficiency.

scholarly journals Challenges in Interpretation of Thyroid Function Tests in Pregnant Women with Autoimmune Thyroid Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Ulla Feldt-Rasmussen ◽  
Anne-Sofie Bliddal Mortensen ◽  
Åse Krogh Rasmussen ◽  
Malene Boas ◽  
Linda Hilsted ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Function ◽  
Thyroid Diseases ◽  
Interindividual Variation ◽  
Reference Ranges ◽  
Thyroid Function Tests ◽  
Autoimmune Thyroid ◽  
Function Tests ◽  
Serum Tsh ◽  
In Pregnancy

Physiological changes during gestation are important to be aware of in measurement and interpretation of thyroid function tests in women with autoimmune thyroid diseases. Thyroid autoimmune activity is decreasing in pregnancy. Measurement of serum TSH is the first-line screening variable for thyroid dysfunction also in pregnancy. However, using serum TSH for control of treatment of maternal thyroid autoimmunity infers a risk for compromised foetal development. Peripheral thyroid hormone values are highly different among laboratories, and there is a need for laboratory-specific gestational age-related reference ranges. Equally important, the intraindividual variability of the thyroid hormone measurements is much narrower than the interindividual variation (reflecting the reference interval). The best laboratory assessment of thyroid function is a free thyroid hormone estimate combined with TSH. Measurement of antithyroperoxidase and/or TSH receptor antibodies adds to the differential diagnosis of autoimmune and nonautoimmune thyroid diseases.

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