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Thyroid : Official Journal of the... Feb 1999Resistance to thyroid hormone (RTH) is a syndrome of elevated serum thyroxine, inappropriately "normal" serum thyrotropin (TSH) and reduced thyroid hormone...
Resistance to thyroid hormone (RTH) is a syndrome of elevated serum thyroxine, inappropriately "normal" serum thyrotropin (TSH) and reduced thyroid hormone responsiveness associated with point mutations in the thyroid hormone receptor-beta (TRbeta) gene. We describe a novel point mutation resulting in a cytosine for adenine substitution at nucleotide 1271 (exon 9) that results in the substitution of threonine for asparagine (T329N). This mutation was identified in a 30-year-old woman who was investigated for recurrent spontaneous abortions and was found to have RTH. Dextrothyroxine (D-T4) therapy was instituted. At 8 mg per day 2 pregnancies followed with the delivery of a healthy boy and an RTH-affected girl another miscarriage occurred on D-T4 treatment at 6 mg per day. The T329N mutation, which was also identified in the daughter, markedly reduces the affinity of TRbeta for triiodothyronine (T3). Formation of T329N mutant TR homodimers and heterodimers with RXRalpha on thyroid hormone response element F2 (TRE F2) was not affected, but the ability of T3 to interrupt T329N mutant TRbeta homodimerization was markedly reduced. The T329N mutant TRbeta was transcriptionally inactive in transient expression assays. In cotransfection assays with wild-type TRbeta1, the mutant TRbeta1 functioned in a dominant negative manner. The results suggest that the T329N mutation in the T3-binding domain of TRbeta is responsible for RTH in the proposita's family.
Topics: Abortion, Habitual; Adult; Dextrothyroxine; Dimerization; Female; Humans; Male; Pedigree; Point Mutation; Pregnancy; Pregnancy Outcome; Receptors, Thyroid Hormone; Sequence Analysis, DNA; Thyroid Hormone Resistance Syndrome; Thyrotropin; Thyroxine; Transcriptional Activation; Triiodothyronine
PubMed: 10090317
DOI: 10.1089/thy.1999.9.165 -
Journal of Immunology (Baltimore, Md. :... Jul 1998We have investigated the mechanism by which thyroid hormone potentiates IFN-gamma-induced HLA-DR expression. IFN-gamma-induced HLA-DR expression requires activation of...
We have investigated the mechanism by which thyroid hormone potentiates IFN-gamma-induced HLA-DR expression. IFN-gamma-induced HLA-DR expression requires activation of STAT1alpha and induction of the Class II trans-activator, CIITA. HeLa and CV-1 cells treated only with L-thyroxine (T4) demonstrated increased tyrosine phosphorylation and nuclear translocation (= activation) of STAT1alpha; this hormone effect on signal transduction, and T4 potentiation of IFN-gamma-induced HLA-DR expression, were blocked by the inhibitors CGP 41251 (PKC) and genistein (tyrosine kinase). Treatment of cells with T4-agarose also caused activation of STAT1alpha. In the presence of IFN-gamma, T4 enhanced cytokine-induced STAT1alpha activation. Potentiation by T4 of IFN-gamma action was associated with increased mRNA for both CIITA and HLA-DR, with peak enhancement at 16 h (CIITA), and 2 d (HLA-DR). T4 increased IFN-gamma-induced HLA-DR protein 2.2-fold and HLA-DR mRNA fourfold after 2 d. Treatment with actinomycin D after induction of HLA-DR mRNA with IFN-gamma, with or without T4, showed that thyroid hormone decreased the t(1/2) of mRNA from 2.4 to 1.1 h. HeLa and CV-1 cells lack functional nuclear thyroid hormone receptor. Tetraiodothyroacetic acid (tetrac) and 3,5,3'-triiodo-thyroacetic acid (triac) blocked T4 potentiation of IFN-gamma-induced HLA-DR expression and T4 activation of STAT1alpha. These studies define an early hormone recognition step at the cell surface that is novel, distinct from nuclear thyroid hormone receptor, and blocked by tetrac and triac. Thus, thyroid hormone potentiation of IFN-gamma-induced HLA-DR transcription is mediated by a cell membrane hormone binding site, enhanced activation of STAT1alpha, and increased CIITA induction.
Topics: Biological Transport; Cell Nucleus; Dextrothyroxine; Diiodothyronines; Drug Synergism; Genistein; HLA-DR Antigens; HeLa Cells; Humans; Interferon-Stimulated Gene Factor 3; Interferon-gamma; Nuclear Proteins; Phosphorylation; Protein Kinase C; Protein-Tyrosine Kinases; RNA, Messenger; Thyroxine; Time Factors; Trans-Activators; Transcription Factors; Triiodothyronine; Triiodothyronine, Reverse; Tyrosine
PubMed: 9670962
DOI: No ID Found -
Journal of the American Society of... Jan 1998Uremia raises lipoprotein(a) (Lp(a)) serum concentration and the risk of arteriosclerosis in dialysis patients. The treatment of high Lp(a) levels is not satisfactory... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
Uremia raises lipoprotein(a) (Lp(a)) serum concentration and the risk of arteriosclerosis in dialysis patients. The treatment of high Lp(a) levels is not satisfactory today. The decrease of Lp(a) in hypothyroid patients on L-T4 therapy raised the question of whether dextro-thyroxine (D-thyroxine) reduces not only serum cholesterol, but also Lp(a) serum concentration. In a single-blind placebo-controlled study, the influence of D-thyroxine therapy on Lp(a) serum concentration was evaluated in 30 hemodialysis patients with elevated Lp(a) serum levels. Lp(a) was quantified in parallel by two methods, i.e., rocket immunoelectrophoresis and nephelometry, and apo(a) isoforms were determined by a sensitive immunoblotting technique. Regardless of the apo(a) isoforms, 6 mg/d D-thyroxine reduced elevated Lp(a) levels significantly by 27 +/- 13% in 20 dialysis patients (P < 0.001) compared with 10 control subjects (-9.9 +/- 8.4%). In parallel, D-thyroxine therapy significantly lowered total cholesterol (P < 0.001), LDL cholesterol (P < 0.001), and LDL cholesterol/HDL cholesterol ratio (P < 0.01); raised T4 and T3 serum levels; and suppressed thyroid-stimulating hormone secretion without causing clinical symptoms of hyperthyroidism in any of the patients. D-Thyroxine reduces elevated serum Lp(a) concentration in dialysis patients. The effect in nondialysis patients can be expected but remains to be proven.
Topics: Aged; Cholesterol; Dextrothyroxine; Electrophoresis; Female; Humans; Immunoblotting; Lipoprotein(a); Male; Middle Aged; Nephelometry and Turbidimetry; Osmolar Concentration; Renal Dialysis; Single-Blind Method
PubMed: 9440092
DOI: 10.1681/ASN.V9190 -
Acta Paediatrica (Oslo, Norway : 1992) Mar 1996We report on an 8-year-old boy with pituitary resistance to thyroid hormone (PRTH) having a cysteine for arginine substitution at codon 320 in the TR-beta gene who was...
We report on an 8-year-old boy with pituitary resistance to thyroid hormone (PRTH) having a cysteine for arginine substitution at codon 320 in the TR-beta gene who was presented because of thyrotoxicosis. Due to its suppressive effect on the pituitary thyrotropin secretion, treatment with D-thyroxine (D-T4) was started. After a few days, clinical euthyroidism was achieved but thyroid stimulating hormone secretion was not suppressed. Symptoms of thyrotoxicosis relapsed when therapy was interrupted so that therapy with D-T4 was reinstituted and continued to date. Symptoms did not recur, and the psychomotor development proceeded normally. D-T4 should therefore be considered in the treatment of thyrotoxicosis in PRTH.
Topics: Amino Acid Sequence; Child; Dextrothyroxine; Humans; Male; Molecular Sequence Data; Mutation; Thyroid Hormone Resistance Syndrome; Thyrotoxicosis; Treatment Outcome
PubMed: 8696005
DOI: 10.1111/j.1651-2227.1996.tb14043.x -
Biochemical Pharmacology Nov 1995Oxidized lipoproteins have been implicated as important factors in the pathogenicity of atherosclerosis. Thus, antioxidants play a significant role in inhibiting a...
Oxidized lipoproteins have been implicated as important factors in the pathogenicity of atherosclerosis. Thus, antioxidants play a significant role in inhibiting a critical step in atheroma progression. Previously, we demonstrated that thyronine analogs inhibit Cu(2+)-induced low density lipoprotein (LDL) oxidation. In the present study, we examined the effect of thyronine analogs on endothelial cell (EC)-induced LDL oxidation. LDL was incubated with or without EC in the presence or absence of various concentrations of thyronine, vitamin C, or probucol at 37 degrees in a humidified atmosphere (95% air, 5% CO2). Thyronine analogs, probucol, and vitamin C inhibited EC-induced LDL oxidation in a concentration-dependent manner. The concentration of each agent (microM) producing 50% inhibition (IC50) of EC-induced LDL oxidation for thiobarbituric acid reactive substances (TBARS) and electrophoretic mobility, respectively, was as follows: 0.294 and 0.417 for levothyroxine (L-T4); 0.200 and 0.299 for L-triiodothyronine (L-T3); 0.125 and 0.264 for dextro-thyroxine (D-T4); 0.203 and 0.304 for reversed triiodothyronine (rT3); 1.02 and 1.44 for probucol; and 13.6 and 14.9 for vitamin C. Thyroid binding globulin (TBG) inhibited EC-induced LDL oxidation; further, thyronines bound to TBG exhibited more antioxidant activity than unbound thyronines. Pretreatment of EC with any of the thyronines decreased the ability of EC to oxidize LDL. Also, our results showed that a synergistic interaction exists between vitamin C and T4 in the inhibition of EC-induced LDL oxidation. The T4 and TBG concentrations that inhibited LDL oxidation were in the physiological range. We conclude that T4, like the pharmacological agent probucol, reduces oxidative modification of LDL and thus may act as a natural inhibitor of atherogenesis.
Topics: Anticholesteremic Agents; Antioxidants; Ascorbic Acid; Capillaries; Cells, Cultured; Drug Interactions; Endothelium, Vascular; Humans; Kinetics; Lipoproteins, LDL; Oxidation-Reduction; Probucol; Thiobarbituric Acid Reactive Substances; Thyroxine; Thyroxine-Binding Proteins
PubMed: 7503765
DOI: 10.1016/0006-2952(95)02047-0 -
Circulation Apr 1995There has been a continuing debate about the overall benefit of cholesterol lowering. We performed a novel meta-analysis of all randomized trials of more than 2 years'... (Comparative Study)
Comparative Study Meta-Analysis
BACKGROUND
There has been a continuing debate about the overall benefit of cholesterol lowering. We performed a novel meta-analysis of all randomized trials of more than 2 years' duration (n = 35 trials) to describe how coronary-heart-disease (CHD), non-CHD, and total mortality are related to cholesterol lowering and to type of intervention.
METHODS AND RESULTS
The analytic approach was designed to separate the effects of cholesterol lowering itself from the other effects of the different types of intervention used. For every 10 percentage points of cholesterol lowering, CHD mortality was reduced by 13% (P < .002) and total mortality by 10% (P < .03). Cholesterol lowering had no effect on non-CHD mortality. Certain types of intervention had specific effects independent of cholesterol lowering. Fibrates (clofibrates, 7 trials; gemfibrozil, 2 trials) increased non-CHD mortality by about 30% (P < .01) and total mortality by about 17% (P < .02). Hormones (estrogen, 2 trials; dextrothyroxin, 2 trials) increased CHD mortality in men by about 27% (P < .04), non-CHD mortality by about 55% (P < .03), and total mortality by about 33% (P < .01). No specific effects independent of cholesterol lowering were found due to diet (n = 11) or other interventions (resins, 5; niacin, 3; statins, 2; partial ileal bypass, 1).
CONCLUSIONS
The results suggest that cholesterol lowering itself is beneficial but that specific adverse effects of fibrates and hormones increase the risk of CHD (hormones only), non-CHD, and total mortality.
Topics: Cholesterol; Cholesterol, Dietary; Clofibrate; Coronary Disease; Dextrothyroxine; Estrogens; Gemfibrozil; Humans; Hypercholesterolemia; Male
PubMed: 7697857
DOI: 10.1161/01.cir.91.8.2274 -
Neurochemistry International Nov 1994The effects of thyroxine and its related derivatives on gamma-aminobutyric acid (GABA) receptors in the rat brain were examined. D-Thyroxine strongly inhibited...
The effects of thyroxine and its related derivatives on gamma-aminobutyric acid (GABA) receptors in the rat brain were examined. D-Thyroxine strongly inhibited [3H]flunitrazepam binding to benzodiazepine receptor in crude synaptic membrane from the rat brain. The Scatchard analysis of the [3H]flunitrazepam binding in the presence of D-thyroxine indicated the decreases in the affinity and maximum number of binding site. Furthermore, D-thyroxine inhibited the enhancing effect of flunitrazepam on GABA-stimulated 36Cl- influx into membrane vesicles, although GABA-stimulated 36Cl- influx alone was not affected by D-thyroxine. On the other hand, the effects of thyroxine and its related derivatives on cerebral GABAB receptor binding were not noted. These results suggest that D-thyroxine may be a drug which is able to modulate the function of GABAA receptor complex via the inhibitory action on benzodiazepine recognition site.
Topics: Animals; Benzodiazepines; Binding Sites; Brain; Chlorides; Dextrothyroxine; Dose-Response Relationship, Drug; Fenclonine; Flunitrazepam; GABA-A Receptor Antagonists; GABA-B Receptor Antagonists; In Vitro Techniques; Rats; Rats, Wistar; Receptors, GABA-A; Receptors, GABA-B; Synaptic Membranes; Thyroxine; Triiodothyronine
PubMed: 7849573
DOI: 10.1016/0197-0186(94)90021-3 -
Acta Endocrinologica Oct 1993A unique thyrotrophin (TSH)-secreting pituitary tumour is described in a patient with a history of recurrent thyrotoxicosis. Unlike other previously reported TSHomas,...
A unique thyrotrophin (TSH)-secreting pituitary tumour is described in a patient with a history of recurrent thyrotoxicosis. Unlike other previously reported TSHomas, the tumour is insensitive to octreotide, a somatostatin analogue. It does not accumulate [111In]octreotide but expresses functional dopamine receptors and responds to the D-isomer of thyroxine, two characteristics beneficial in the management of the patient.
Topics: Bromocriptine; Dextrothyroxine; Dopamine Agents; Drug Resistance; Female; Humans; Middle Aged; Octreotide; Pituitary Neoplasms; Radionuclide Imaging; Thyrotoxicosis; Thyrotropin; Tomography, X-Ray Computed
PubMed: 7901958
DOI: 10.1530/acta.0.1290291 -
Lancet (London, England) Jun 1993
Topics: Dextrothyroxine; Drug Contamination; Humans; Thyroidectomy
PubMed: 8099168
DOI: 10.1016/0140-6736(93)90922-4 -
Thyroid : Official Journal of the... 1992The dextroisomer of thyroxine (D-T4) has been shown to have suppressive effects on pituitary TSH secretion in euthyroid individuals and patients with mild thyroid...
The dextroisomer of thyroxine (D-T4) has been shown to have suppressive effects on pituitary TSH secretion in euthyroid individuals and patients with mild thyroid hormone resistance. We treated a 3-year-old boy with D-T4 who was homozygous for a T3 receptor defect, resulting in a complex clinical picture of tissue-specific hyperthyroidism and hypothyroidism. There was no evidence of significant alteration in thyroid physiology, including serum concentrations of basal and TRH stimulated TSH or echocardiographic parameters measuring systolic time interval. We conclude that D-T4 at a daily dose of 6 mg (0.65 mg/kg) was ineffective in this boy with homozygous dominant negative thyroid hormone resistance.
Topics: Child, Preschool; Dextrothyroxine; Drug Resistance; Humans; Hyperthyroidism; Hypothyroidism; Longitudinal Studies; Male; Pituitary Gland; Receptors, Thyroid Hormone; Thyrotropin; Thyrotropin-Releasing Hormone; Thyroxine; Triiodothyronine
PubMed: 1525565
DOI: 10.1089/thy.1992.2.15