Clinical study on early changes in thyroid function of hyperthyroidism treated with propylthiouracil and a relatively small dose of iodide.
(25/3109)
In order to compare the acute effects of three kinds of antithyroid agents of iodide (I-), propylthiouracil (PTU) and PTU combined with iodide (PTU+I-) on thyroid function in hyperthyroid patients with diffuse goiter, serum concentrations of thyroxine (T4), triiodothyronine (T3), T3-resin sponge uptake (T3-RU) and free thyroxine index (FT4I) were employed as thyroid function parameters. In the group given iodine (1 mg/day) as iodinated-lecithine, the initial values of T4, T3, T3-RU and FT4I were 20.9 +/- 1.6 microng/100 ml (T4), greater than 740 ng/100 ml (T3), 49.5 +/- 2.3% (T3-RU) and 14.7 +/- 1.8 (FT4I). At the end of one week of therapy, they decreased clearly to 15.6 +/- 2.2 microng/100 ml, 457 +/- 87 ng/100 ml, 42.2 +/- 4.0% and 9.7 +/- 2.4. The so-called "escape phenomenon" from iodide inhibition was observed in serum T4, T3-RU and FT4I values at the end of two weeks of iodide therapy, while serum T3 continued to decrease but the value of T3 was far outside of the normal range. In the PTU group (300 mg/day), thyroid function parameters were 22.5 +/- 0.8 microng/100 ml (T4), greater than 592 ng/100 ml (T3), 54.9 +/- 1.0% (T3-RU) and 18.7 +/- 1.0 (FT4I) before treatment. They decreased continually week by week. At the end of four-week treatment with PTU, the value of each thyroid function parameter was 11.1 +/- 1.9 microng/100 ml, 229 +/- 56 ng/100 ml, 36.6 +/- 4.4% and 5.7 +/- 1.7. In the group of hyperthyroidism simultaneously given both PTU and iodide (300 mg/PTU and 1 mg/iodine), these thyroid function parameters decreased as well as in the group treated with PTU alone for more than two weeks. More rapid or significant decrease of T4, T3, T3-RU and ft4i in PTU+I- group than in PTU group was observed in the present study. These results suggested strongly that iodide alone was not an adequate therapy for hyperthyroidism as well known and they were also compatible with the idea that the concomitant administration of PTU and iodide was more effective in the early phase of therapy of hyperthyroidism than PTU alone. (+info)
Reduction of thyroid hormone levels by methylsulfonyl metabolites of tetra- and pentachlorinated biphenyls in male Sprague-Dawley rats.
(26/3109)
Male Sprague-Dawley rats received four consecutive intraperitoneal (i.p.) doses of five kinds of methylsulfonyl (MeSO2) metabolites of tetra- and pentachlorinated biphenyls (tetra- and pentaCBs) to determine their effects on thyroid hormone levels. The five MeSO2 metabolites, which were the major MeSO2-PCBs detected in human milk, liver and adipose tissue were 3-MeSO2-2,2',4',5-tetraCB (3-MeSO2-CB49),3-MeSO2-2,3',4',5-tetraCB (3-MeSO2-CB70), 3-MeSO2-2,2',3',4',5-pentaCB (3-MeSO2-CB87), 3-MeSO2-2,2',4',5,5'-pentaCB (3-MeSO2-CB101), and 4-MeSO2-2,2',4',5,5'-pentaCB (4-MeSO2-CB101). All five tested MeSO2 metabolites (20 mumol/kg once daily for 4 days) reduced serum total thyroxine levels 16-40% on days 2, 3, 4, and 7 (after the last dosage). The total triiodothyronine level was reduced 37% by treatment with 3-MeSO2-CB49 at day 7, but was increased 35% and 38% by 3-MeSO2-CB70 and 4-MeSO2-CB101 at days 3 and 4, respectively. The reductions in thyroid hormone levels led to an increase in thyroid stimulating hormone (TSH) levels by 3-MeSO2-CB49, 3-MeSO2-CB87 and 3-MeSO2-CB101. A 30% increase in thyroid weight was produced by 3-MeSO2-CB101 treatment. Thus, it is likely that all five tested MeSO2 metabolites could influence thyroid hormone metabolism. The results show that the tested 3- and 4-MeSO2 metabolites of tetra- and pentaCBs reduce thyroid hormone levels in rats, suggesting that the metabolites may act as endocrine-disrupters. (+info)
Tri-iodothyronine increases insulin-like growth factor binding protein-2 expression in cultured hepatocytes from hypothyroid rats.
(27/3109)
Previous evidence suggests the existence of a thyroid hormone-IGF axis in the liver and changes in hepatic insulin-like growth factor binding protein (IGFBP) expression in rats with altered thyroid status have been previously reported. The aim of this study was to check if the higher IGFBP-2 mRNA levels observed in liver of hypothyroid rats could be due to a direct effect of thyroid hormone on the IGFBP-2 gene. In our experiments, cultured hepatocytes isolated from normal and hypothyroid adult rats were used. Northern blot analysis revealed barely detectable IGFBP-2 mRNA in normal rat hepatocytes, but easily detectable signal in hypothyroid rat cells. Therefore, the effect of tri-iodothyronine (T3) was investigated using cultured hepatocytes from hypothyroid rats as an in vitro model. The IGFBP-2 message was increased in a dose-dependent manner in hepatocytes cultured for 12-24 h in the presence of T3. A similar increase occurred in accumulation of IGFBP-2 in the culture medium, as measured by RIA. The effect of T3 on IGFBP-2 transcript levels appeared to consist of enhanced gene transcription and was independent of ongoing protein synthesis, but it was completely abolished by the incubation of hepatocytes with insulin. The latter result confirmed the dominant role of insulin in regulating IGFBP-2 expression by cultured hepatocytes. In vivo experiments confirmed an increase in hepatic IGFBP-2 mRNA and serum IGFBP-2 levels in hypothyroid rats and demonstrated, in addition, a significant increase in these measures in T3-treated rats. Taken together, our in vitro and in vivo results support a role for a thyroid hormone-IGF axis in the liver and suggest that other factors, such as insulin, interact in vivo with thryoid hormone in regulating hepatic IGFBP-2 expression. (+info)
Regulation of differentiation of sheep subcutaneous and abdominal preadipocytes in culture.
(28/3109)
Factors regulating the differentiation of sheep subcutaneous and abdominal (omental or perirenal) preadipocytes from foetal lambs, suckling lambs and fattening sheep have been investigated using a serum-free cell culture system. Differentiation was assessed by changes in the activity of the enzyme glycerol 3-phosphate dehydrogenase. Insulin or IGF-I was essential for differentiation. Dexamethasone, a lipid supplement (Excyte) and the thiazolidinedione, rosiglitazone (BRL 49653) (a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist) all enhanced preadipocyte differentiation, whereas fibroblast growth factor and GH were inhibitory. The most effective combination was insulin, triiodothyronine, dexamethasone and rosiglitazone. Under suboptimal conditions, preadipocytes from fattening sheep differentiated less well than cells from suckling and foetal lambs. Also, under suboptimal conditions, abdominal preadipocytes did not differentiate as well as subcutaneous preadipocytes. However, age and depot differences were minimised when cells were cultured with insulin, triiodothyronine, rosiglitazone and either dexamethasone or lipid. The results suggest that variation in the ability to produce the natural ligand for PPAR-gamma contributes to depot- and age-specific differences in the ability of preadipocytes to differentiate. (+info)
Effect of mutations in the beta1-thyroid hormone receptor on the inhibition of T3 binding by desethylamiodarone.
(29/3109)
Desethylamiodarone (DEA) acts as a competitive inhibitor of triiodothyronine (T3) binding to the alpha1-thyroid hormone receptor (TR alpha1) but as a non-competitive inhibitor with respect to TR beta1. To gain insight into the position of the binding site of desethylamiodarone on TR beta1 we investigated the naturally occurring mutants Y321C, R429Q, P453A, P453T and the artificial mutants L421R and E457A in the ligand binding domain of human TR beta1. The IC50 values (in microM) of DEA for P453A (50 +/- 11) and P453T (55 +/- 16) mutant TR beta1 are not different from that for the wild type TR beta1 (56 +/- 15), but the IC50 values of R429Q (32 +/- 7; P<0.001) and E457A (17 +/- 3; P<0.001) are significantly lower than of the wild type. Scatchard plots and Langmuir analyses indicate a non-competitive nature of the inhibition by DEA of T3 binding to all four mutant TR beta1s tested. Mutants P453A and P453T do not influence overall electrostatic potential, and also do not influence the affinity for DEA compared to wild type. Mutant E457A causes a change from a negatively charged amino acid to a hydrophobic amino acid, enhancing the affinity for DEA. Mutant R429Q, located in helix 11, causes an electrostatic potential change from positive to uncharged, also resulting in greater affinity for DEA. We therefore postulate that amino acids R429 and E457 are at or close to the binding site for DEA, and that DEA does not bind in the T3 binding pocket itself, in line with the non-competitive nature of the inhibition of T3 binding to TR beta1 by DEA. (+info)
Glucose and amino acids interact with hormones to control expression of insulin-like growth factor-I and growth hormone receptor mRNA in cultured pig hepatocytes.
(30/3109)
Nutrients and hormones are major determinants of animal growth, but the mechanisms of how nutrients influence the growth process are still unclear. A primary pig hepatocyte culture system was used to investigate possible direct effects of glucose and individual amino acids on the expression of growth hormone receptor (GHR) and insulin-like growth factor-I (IGF-I) mRNA. The removal of glucose from the culture medium for 40 h resulted in significant reductions (to 45% of control, P = 0.013) in the expression of GHR in the presence of growth hormone (GH), dexamethasone (DEX) and tri-iodothyronine (T3). The decrease in GHR expression with removal of glucose from the culture medium resulted in a decreased response in class 1 (22% of control, P = 0.011) and 2 (5% of control P = 0. 068) transcripts of IGF-I to any GH added. The effects of glucose on GHR and IGF-I expression were dose-dependent, appearing to plateau at approximately 1-2 g/L (P = 0.031, for quadratic trend). Removal of arginine, proline, threonine, tryptophan or valine inhibited the stimulation of IGF-I expression that was induced by the combination of T3, DEX and GH (to 15, 6, 11, 16 and 16% of control, respectively, P < 0.05), with significant decreases in GHR expression also observed in some cases. The stimulatory effect of some of these amino acids (arginine, proline, threonine and tryptophan) was dose-dependent for expression of class 1 transcripts of IGF-I (P = 0. 041, 0.022, 0.016 and 0.097, respectively, for linear trends), but there was no effect on GHR or class 2 transcripts of IGF-I. Whether the observed effects of nutrients on mRNA levels are due to direct effects on gene transcription or differences in mRNA stability remains to be established. Energy, in the form of glucose, appears to control GHR expression, interacting with the effects of glucocorticoids and thyroid hormones, whereas protein, in the form of certain individual amino acids, appears to control GH-stimulated IGF-I expression. (+info)
Energy intake and utilization vary during development in rats.
(31/3109)
Energy intake, utilization, and partitioning were determined in male Wistar rats from 25 to 180 d of age. Serum free triiodothyronine, leptin, and free fatty acid concentrations were also measured. Energy balance measurements allowed us to identify a period from 25 to 90 d, characterized by a rapid body growth rate and another from 90 to 180 d, during which body growth rate slowed. From 25 to 180 d, we found decreases in daily energy intake and expenditure, which were faster before 90 d. The first period was characterized by storage of lipid and protein. In the second period, protein deposition approached zero and the excess of ingested energy was entirely stored as fat, so that age-associated obesity began to develop. The inability of rats to maintain a stable body weight after the cessation of growth of lean body mass is not due to decreased resting metabolism but rather to a partial leptin resistance. (+info)
A case of Graves' disease associated with autoimmune hepatitis and mixed connective tissue disease.
(32/3109)
The patient was a woman of forty-eight. Liver dysfunction was pointed out at the age of forty-five. She was admitted to hospital because of her hyperthyroidism. Her palmar skin was wet and her fingers were swollen like sausages. She had a diffuse and elastic hard goiter with a rough surface. The serum levels of free T3 (9.6 pg/mL) and free T4 (3.76 ng/dL) were high and that of TSH (0.11 microU/mL) was low. The activity of TSH-binding inhibitory immunoglobulin (TBII) was 89%. The uptake rate of 123I to the thyroid was 55.1% and the uptake pattern was nearly diffuse. The goiter was proved to contain several nodules by ultrasonography, but aspiration cytology showed no malignant cells. She was diagnosed to have Graves' disease with adenomatous goiter. She also had high ALT (34 IU/L) and gamma-globulin (1.97 g/dL). She had positive antinuclear antibody (speckled type), positive anti-ribosomal nuclear protein antibody, and positive LE cell phenomenon. The liver biopsy revealed mononuclear cell infiltration with fibrosis in the portal area. These data indicated that she also had autoimmune hepatitis (AIH) and mixed connective tissue disease (MCTD). The analysis of human leukocyte antigen (HLA) showed positive A11 which had been reported to relate to Graves' disease, and positive DR4 which had been reported to relate to AIH and MCTD. These results suggested that HLA would determine susceptibility to three distinct autoimmune diseases in this case. (+info)