Use of anti-thyroid drugs in euthyroid pregnant women with previous Graves' disease.
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Euthyroid pregnant women with a previous history of Graves' disease treated with radioiodine or surgery may have persistently elevated TSH receptor antibody (TRAb) levels, putting their offspring at risk for fetal hyperthyroidism (FH) and/or neonatal hyperthyroidism (NH).We performed a literature review using a MEDLINE search to determine if and how anti-thyroid drugs (ATD) were utilized in euthyroid pregnant women with previous Graves' disease to prevent FH/NH.There are 11 published reports involving 13 pregnancies where ATDs were utilized to prevent FH in euthyroid mothers with a previous history of Graves' disease. Subjects were treated if high titres of TRAb (> 5-fold above normal) were noted on either radioreceptor assay or various bioassays. Such intervention appeared beneficial. Thirteen live births were observed when previously these mothers collectively experienced six miscarriages, stillborn or infant deaths attributed to FH or NH. Developmental consequences such as craniosynostosis or dysmorphic features were not observed in the infants described. Both propylthiouracil and methimazole were used effectively. When utilized, cordocentesis (or periumbilical blood sampling) to determine fetal thyroid status and TRAb levels proved to be of value in establishing the diagnosis and guiding therapy.Maternal ATD prevent the serious consequences of FH/NH and should be considered for euthyroid Graves' mothers with high TRAb titres.Keywords:
Trab
Propylthiouracil
Antithyroid agent
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In Graves' patients complicated by pregnancy, both maternal and fetal problems related to the disease can be reduced or avoided by controlling hyperthyroidism. However, optimal treatment for mothers may exert detrimental effects on fetuses. Methimazole may cause "methimazole embryopathy". Antithyroid drug doses that maintain mothers in euthyroid status are sometimes excessive fetuses. Furthermore, successful treatment with surgery or radioiodine occasionally may result in fetal hyperthyroidism due to TSH receptor antibody(TRAb). There are approaches to manage these problems. Propylthiouracil is chosen in treating Graves' disease in early pregnancy. In later pregnancy, maternal free thyroxine is maintained near or somewhat above normal. Ablative therapy is not recommended in women whose TRAb levels are extremely high from the standpoint of fetal thyroid state.
Trab
Propylthiouracil
Antithyroid agent
Methimazole
Thyrotropin receptor
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ABSTRACT Serum thyroglobulin (Tg), measured by radioimmunoassay, was high in 6-propylthiouracil (PTU)-treated rats but low in thyroxine (T 4 )-treated animals compared with euthyroid controls. Thyroid-stimulating hormone (TSH) stimulated Tg release in vitro from enzymatically dispersed normal rat thyroid cells in a dose-dependent manner. Thyroid cells prepared from T 4 -treated animals behaved similarly to cells from control rats, whereas in vitro basal release of Tg from thyroid cells prepared from PTU-treated animals was high and the response to TSH was lost. Our data confirm the TSH dependency of Tg release in vivo and in vitro and our system provides a means of studying the control of Tg secretion in vitro . J. Endocr. (1984) 101 , 107–111
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Thyroglobulin
Basal (medicine)
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The effects of the feeding of high-iodine eggs to rats with an abnormal thyroid status were investigated. Rats were fed for one week on a commercial diet supplemented with propylthiouracil (PTU) (10 mg/100 g diet) or thyroxine-Na (240 micrograms/100 g diet) respectively, to induce hypo- or hyperthyroidism, and then further fed for 4 weeks on the respective drug-supplemented diets, containing 1% (w/w) of either ordinary or high-iodine egg powder. Control (euthyroid) rats were maintained on the commercial diet. The induction of a hypothyroid state resulted in thyroid hyperplasia, with decreased thyroid iodine content, altered serum thyroid relating hormone levels (increased TSH and decreased T3 and T4), elevated serum total cholesterol and reduced serum triacylglycerol (TG) levels, and also increased muscle and adipose tissue lipoprotein lipase (LPL) activities. In contrast, in the hyperthyroid animals, thyroid atrophy, as well as decreased serum TSH and increased T3 and T4 levels, was associated with reduced serum total cholesterol level and muscle LPL activity. There were no essential differences between animals given high-iodine and ordinary eggs in either hypo- or hyperthyroid state, although the effects of PTU treatment on the thyroid and serum TG level appeared to be slightly lesser in rats given high-iodine eggs than in those given ordinary eggs. It is concluded that high-iodine eggs did not have any side-effect on either hypo- or hyperthyroid rat in this study.
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Propylthiouracil (PTU) administered to pregnant rats from day 18–21 of gestation caused a significant increase in maternal and fetal thyroid weight and plasma TSH. Fetal encephalectomy on day 18 did not significantly affect basal or PTU-stimulated pituitary- thyroid function. Destruction of the basal hypothalamus in the mother on day 13 or 16 markedly reduced maternal plasma TSH and thyroxine and prevented a PTU-induced increase in thyroid size, but did not affect fetal pituitary-thyroid function. Plasma PRL was undetectable in both intact and encephalectomized fetuses at 21 days but was increased > 6-fold to approximately 2 μg/ml in the mothers by maternal hypothalamic destruction. We conclude that fetal pituitary-thyroid function in the rat is not dependent on either fetal or maternal hypothalamic TRH. (Endocrinology102: 852, 1978)
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Earlier studies have shown larger increments in serum T3 in 2-week-old congenitally hypothyroid rats than in euthyroid controls after injections of small doses of T4. Since hepatic and renal 5′-deiodination of T4 to T3 in vitro (5′D-I) is reduced during the neonatal period and in hypothyroidism, those results suggest that there may be major changes in the distribution and metabolism of T3 or that an alternative enzymatic pathway is the predominant source of extrathyroidally produced T3 in these rats. The alternative pathway, 5′D-II, is a relatively minor source of serum T3 in adult euthyroid rats, but the contribution of this pathway to the extrathyroid T3 pool during the neonatal period and in hypothyroxinemia is not known. Consequently, we studied [125I]T4 and [131I]T3 kinetics and fractional T4 to T3 conversion in 2-week-old euthyroid and hypothyroid rats and then explored the source of circulating T3 by manipulating 5′D-I activity with propylthiouracil and that of 5′D-II with thyroid hormone. The plasma clearance rate of T4 was increased in hypothyroid rats, a difference entirely accounted for by the faster fractional rate of irreversible removal in the hypothyroid pups. Plasma clearance rate of T3 was reduced in hypothyroid rats owing to the reduced volume of distribution of T3. Fractional T4 to T3 conversion was 2- to 3-fold higher in euthyroid or hypothyroid neonates than in adult rats. In euthyroid rats the serum concentration of T4 was 36 ± 1 (sem) ng/ml and that of T3 0.61 ± 0.03 ng/ml, and the production rates were 432 and 159 ng day−1 30 g−1 BW for T4 and T3, respectively. About 80% of the T3 in euthyroid neonates was produced extrathyroidally. These findings are inconsistent with hepatic and renal 5′D-I being the main source of serum T3 in 2-week-old rats. In fact, liver and kidney 5′D-I activities were 40% and 65% of the corresponding adult values in euthyroid neonates, and in hypothyroid pups were further reduced to 15% and 17%. In contrast, 5′D-II, previously reported to be high in central nervous tissue and pituitary, was 7–10-fold higher in brown adipose tissue (BAT) of hypothyroid pups than in that of euthyroid ones. Doses of propylthiouracil that inhibited liver and kidney 5′ D-I greater than or equal to 90% decreased fractional conversion of [125I]T4 to [125I]T3 only by 25% in euthyroid and not at all in hypothyroid neonatal rats. In contrast, a single dose of 1.8 μg T4/100 g BW, given 25 h before the tracers to hypothyroid pups, reduced [125I]T3 generation by 30%. This dose of T4 decreased 5′D-II by 63% in interscapular BAT, but did not affect liver or kidney 5′D-I. We conclude that a 5′D-II pathway is the predominant mechanism for extrathyroid T3 production in the euthyroid neonate and the only pathway demonstrable in the hypothyroid neonate. In these situations 5′D-II is not only responsible for local T3 production in brain and pituitary, as in the adult rat, but also for most of circulating T3. The significant amounts of 5′D-II in BAT, and the responses of 5′D-II to hypothyroidism and adrenergic stimulation in this tissue, suggest that BAT may be an important site of T3 production in the neonate. (Endocrinology 115: 2394, 1984)
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Thyroid disease is often accompanied by changes in the concentrations of serum lipids and lipoproteins. To evaluate the hepatic contribution to the serum abnormalities in thyroid disease, we examined fatty acid metabolism in perfused livers from pair-fed rats made hypothyroid with propylthiouracil (PTU) or made hyperthyroid by treatment with triiodothyronine (T3). The animals treated with T3 became hyperphagic, depending on dose of drug and duration of hyperthyroidism. It was necessary, therefore, for appropriate controls, that food intake of T3-treated rats be restricted to quantities consumed by euthyroid rats. Animals treated with PTU for 2 wk became hypophagic, and therefore, food consumption of controls was restricted to that eaten by rats receiving PTU. Dependent on dose of T3 and duration of treatment, the output of triglyceride and glucose was diminished, whereas output of ketone bodies was increased by livers from hyperthyroid animals. In contrast, livers from PTU-treated animals secreted increased amounts of triglyceride and glucose, whereas ketogenesis was diminished. The best models for study proved to be animals treated with either 10 μg T3/100 g body wt per d or 1 mg PTU/100 g body wt per d for 7 d. Under these conditions, all animals consumed the same quantity of food as did the euthyroid rats, but continued to display the metabolic alterations outlined above. The effects of PTU on hepatic metabolism were readily reversible by simultaneous administration of T3. It is clear from these data that the thyroid status of the rat regulates hepatic triglyceride formation and secretion, and ketogenesis.
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Ketogenesis
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Expression of the cardiac Na(+)-Ca2+ exchanger (NCX) is high at birth and declines rapidly to adult levels by approximately 21 days in rabbits. The aim was to evaluate the role of thyroid hormone in regulating cardiac NCX expression.Adult New Zealand White rabbits were made hypothyroid by treatment with propylthiouracil or hyperthryoid by administration of sigma-thyroxine. Hypothyroidism was induced in immature rabbits by exposure to propylthiouracil from gestational day 25 through the first 21 days after birth. NCX steady-state mRNA levels were quantitated using Northern slot blots with poly(A+) RNA isolated from ventricular myocardium of treated and age-matched euthyroid animals. As a control, steady-state levels of cardiac sarco(endo)plasmic reticulum calcium ATPase (SERCA2a) were measured in each group. Thyroid status was confirmed with serum T4, ventricular weight and body weight measurements. Immunoreactive NCX protein levels were assessed using Western blots.Compared with euthyroid controls, NCX steady-state mRNA levels increased to 189 +/- 20% in hypothyroid adults and decreased to 55 +/- 15% in hyperthyroid adults. Opposite effects were observed for SERCA2a expression (58 +/- 7% in hypothyroidism and 130 +/- 15% in hyperthyroidism). In hypothyroid 21-day-old rabbits, NCX steady-state mRNA levels were elevated to 205 +/- 30% of age-matched euthyroid controls. SERCA2a levels were unaffected in the immature animals, possibly due to inability to reduce thyroid levels sufficiently to affect SERCA2a expression in this model. Changes in NCX mRNA levels produced comparable changes in immunoreactive NCX protein levels.Thyroid hormone reciprocally regulates NCX and SERCA2a expression in the ventricles of adult rabbits. Hypothyroidism resulted in sustained high levels of NCX expression in 21-day-old rabbits. These results suggest that the postnatal thyroid hormone surge is important for the normal down-regulation of cardiac NCX expression during the first 3 weeks after birth in developing rabbits.
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The effects of thyroid status on the activity of hepatic cAMP phosphodiesterase (PDE) were studied in the rat. Male rats were rendered hyperthyroid by treatment with T3 or hypothyroid by treatment with propylthiouracil. The hepatic particulate low Km PDE was solubilized, and its activity was measured at concentrations of 0.12-1.3 microM cAMP. The Km decreased in hypothyroidism and tended to increase in hyperthyroidism with respect to individual controls. The maximal velocity (Vmax) was unaffected by changes in thyroid status. The increases in Km correlated with increasing plasma T3, whereas the Vmax did not. Concentrations of cAMP increased in the livers from hyperthyroid rats and decreased in those from hypothyroid, in comparison with euthyroid rat livers. The effects of thyroid status on various aspects of hepatic lipid metabolism reported from this laboratory may, in part, have resulted from alterations in hepatic cAMP concentrations. These alterations, may have resulted secondarily from changes in the activity of hepatic PDE by changes in the Km for cAMP with little change in the Vmax.
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Treatment with propylthiouracil of euthyroid, hyperthyroid or hypothyroid patients previously given radiothyroxine (and, in one instance, thyroid extract) resulted in a diminution in the rate of disappearance of body radioactivity and serum protein-bound radioiodine. The findings suggest that propylthiouracil interferes with the extrathyroidal metabolism of thyroxine.
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Between the 4th and 10th days of postnatal life in the rat, serum corticosterone levels were low and basal, while the rate of [3H]thymidine incorporation into lung DNA was maximal. From day 13, serum corticosterone levels began to rise significantly, and the lung [3H]thymidine incorporation rate began to fall dramatically; however, these events were obtunded by propylthiouracil-induced hypothyroidism. When 6- to 8-dayold euthyroid pups were given a single sc injection of 10 μg dexamethasone, the rate of DNA synthesis in the lung fell by 96.7% of the initial rate at 24 h. This steroidal effect was blunted in hypothyroid pups and restored by exogenous thyroid hormone. The thyroid status of the pup did not modify the response patterns of lung phosphodiesterase and cytosolic glucocorticoid receptor levels to dexamethasone treatment, although both parameters were influenced by thyroid hormone availability. Radiocholine incorporation into lung phospholipids, which was altered in hypothyroidism, was unaffected by dexamethasone treatment. An in vivo assessment of radiothymidine incorporation into DNA of various tissues in 5-day-old euthyroid pups given 10 μg dexamethasone 24 h earlier revealed that of the several tissues in which inhibition of DNA synthesis was demonstrable, the developing lung was the most sensitive to the antimitogenic steroidal effect. When considered in the light of existing evidence, these observations suggest that glucocorticoids play an important role in triggering lung cytodifferentiation during the third postnatal week in the rat, and that preconditioning of the lung by thyroid hormone optimizes this developmental effect of glucocorticoids.
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