Showing papers on "Propylthiouracil published in 2005"

Biochemical mechanisms of thyroid hormone deiodination

Abstract: Deiodination is the foremost pathway of thyroid hormone metabolism not only in quantitative terms but also because thyroxine (T4) is activated by outer ring deiodination (ORD) to 3,3',5-triiodothyronine (T3), whereas both T4 and T3 are inactivated by inner ring deiodination (IRD) to 3,3',5-triiodothyronine and 3,3'- diiodothyronine, respectively. These reactions are catalyzed by three iodothyronine deiodinases, D1-3. Although they are homologous selenoproteins, they differ in important respects such as catalysis of ORD and/or IRD, deiodination of sulfated iodothyronines, inhibition by the thyrostatic drug propylthiouracil, and regulation during fetal and neonatal development, by thyroid state, and during illness. In this review we will briefly discuss recent developments in these different areas. These have resulted in the emerging view that the biological activity of thyroid hormone is regulated locally by tissue-specific regulation of the different deiodinases.

Oxidative stress and serum paraoxonase activity in experimental hypothyroidism: effect of vitamin E supplementation.

Abstract: Thyroid hormones are associated with the oxidative and antioxidative status of the organism. Since data on the oxidative status of hypothyroidism are limited and controversial, we investigated the oxidant and antioxidant status and serum paraoxonase/arylesterase activities in propylthiouracil-induced hypothyroidism and examined the effect of vitamin E supplementation on this experimental model. Forty male Sprague Dawley rats were randomly divided into four groups (group 1, control; group 2, control + vitamin E; group 3, propylthiouracil; group 4, propylthiouracil + vitamin E). Plasma, red blood cell, liver, heart and skeletal muscle malondialdehyde levels were increased in the propylthiouracil-treated group compared with the control rats and were decreased in propylthiouracil + vitamin E group compared with the propylthiouracil-treated group. Vitamin E supplementation also significantly increased liver and kidney reduced glutathione levels in propylthiouracil treated animals. Serum paraoxonase and arylesterase activities were decreased in propylthiouracil treated group and vitamin E supplementation caused significant increase in serum paraoxonase activity compared with the propylthiouracil-treated rats. These findings suggest that hypothyroidism is accompanied with increased oxidative stress and vitamin E supplementation exerts beneficial effects on this situation.

Mode of Action: Developmental Thyroid Hormone Insufficiency—Neurological Abnormalities Resulting From Exposure to Propylthiouracil

Abstract: Because thyroid hormone is essential for normal brain development before and after birth, environmental chemicals that interfere with thyroid hormone signaling can adversely affect brain development. Adverse consequences of thyroid hormone insufficiency depend both on severity and developmental timing, indicating that environmental antithyroid factors may produce different effects at different developmental windows of exposure. Mechanistic studies can provide important insight into the potential impact of chemicals on human thyroid function, but relevance to humans must be systematically evaluated. This kind of analysis depends on data sets that include information about animals and humans. The drug 6-n-propyl-2-thiouracil (PTU) is used in animals to experimentally manipulate serum thyroid hormone levels, and in humans to treat patients, including pregnant women, with Graves' disease. A systematic analysis of the mode of action (MOA) of PTU in rats and in humans discloses similar modes of action. While the analysis predicts that PTU doses that produce thyroid hormone insufficiency in humans would adversely affect the developing brain, careful monitoring of PTU administration in pregnant and lactating humans keeps infant serum thyroid hormone levels within the normal range.

Thyroid disorders associated with pregnancy: etiology, diagnosis, and management.

Abstract: Pregnancy has an effect on thyroid economy with significant changes in iodine metabolism, serum thyroid binding proteins, and the development of maternal goiter especially in iodine-deficient areas. Pregnancy is also accompanied by immunologic changes, mainly characterized by a shift from a T helper-1 (Th1) lymphocyte to a Th2 lymphocyte state. Thyroid peroxidase antibodies are present in 10% of women at 14 weeks' gestation, and are associated with (i) an increased pregnancy failure (i.e. abortion), (ii) an increased incidence of gestational thyroid dysfunction, and (iii) a predisposition to postpartum thyroiditis. Thyroid function should be measured in women with severe hyperemesis gravidarum but not in every patient with nausea and vomiting during pregnancy. Graves hyperthyroidism during pregnancy is best managed with propylthiouracil administered throughout gestation. Thyroid-stimulating hormone-receptor antibody measurements at 36 weeks' gestation are predictive of transient neonatal hyperthyroidism, and should be checked even in previously treated patients receiving thyroxine. Postpartum exacerbation of hyperthyroidism is common, and should be evaluated in women with Graves disease not on treatment. Radioiodine therapy in pregnancy is absolutely contraindicated. Hypothyroidism (including subclinical hypothyroidism) occurs in about 2.5% of pregnancies, and may lead to obstetric and neonatal complications as well as being a cause of infertility. During the last few decades, evidence has been presented to underpin the critical importance of adequate fetal thyroid hormone levels in order to ensure normal central and peripheral nervous system maturation. In iodine-deficient and iodine-sufficient areas, low maternal circulating thyroxine levels have been associated with a significant decrement in child IQ and development. These data suggest the advisability of further evaluation for a screening program early in pregnancy to identify women with hypothyroxinemia, and the initiation of prompt treatment for its correction. Hypothyroidism in pregnancy is treated with a larger dose of thyroxine than in the nonpregnant state. Postpartum thyroid dysfunction (PPTD) occurs in 50% of women found to have thyroid peroxidase antibodies in early pregnancy. The hypothyroid phase of PPTD is symptomatic and requires thyroxine therapy. A high incidence (25-30%) of permanent hypothyroidism has been noted in these women. Women having transient PPTD with hypothyroidism should be monitored frequently, as there is a 50% chance of these patients developing hypothyroidism during the next 7 years.

The effect of combination therapy with propylthiouracil and cholestyramine in the treatment of Graves’ hyperthyroidism

Abstract: Summary Objective The study aims to evaluate the efficacy of combination therapy with propylthiouracil (PTU) and cholestyramine in the treatment of Graves’ hyperthyroidism. Background Thyroxine (T4) is metabolized mainly in the liver by conjugation to glucuronides and sulphates that enter the enterohepatic circulation. Thyrotoxic patients have an abnormal increase in thyroid hormone in their enterohepatic circulation. Previous studies on combination therapy with methimazole and cholestyramine for Graves’ hyperthyroidism have shown it to be an effective adjunctive treatment. In this study, we examined the efficacy of combination therapy with PTU and cholestyramine in the treatment of Graves’ hyperthyroidism. Methods Thirty patients with newly diagnosed Graves’ hyperthyroidism were randomly divided into two groups: group I (n = 15) received PTU 100 mg twice a day, propranolol 40 mg twice a day and cholestyramine 4 g twice a day for 4 weeks; group II (n = 15) received PTU 100 mg twice a day and propranolol 40 mg twice a day for 4 weeks. The therapeutic efficacy was determined by serum total triiodothyronine (TT3), free thyroxine (FT4) and TRAb levels at baseline, and at the end of 2 and 4 weeks during the study period. Results There was no significant difference in baseline thyroid function parameters. At the end of 2 and 4 weeks of the study period, serum TT3 and FT4 levels of group I were significantly lower than those of group II. No significant differences in the TRAb level were found between the two groups. Conclusion Cholestyramine contributed to a more rapid and complete decline in thyroid hormone levels in patients with Graves’ hyperthyroidism. It was thus proved to be an effective and well-tolerated adjunctive therapy.

Thyroid status and nitric oxide in rat arterial vessels

Abstract: Thyroid disease has profound effects on cardiovascular function. Hypo- and hyperthyroidism, for example, are associated with reduced and increased maximal endothelium-dependent vasodilation respectively. We therefore hypothesized that the capacity for vascular nitric oxide (NO) formation is decreased in hypothyroidism and increased in hyperthyroidism. To test this hypothesis, rats were made hypothyroid (HYPO) with propylthiouracil or hyperthyroid (HYPER) with triiodothyronine over 3–4 months. Compared with euthyroid control rats (EUT), HYPO exhibited blunted growth and lower citrate synthase activity in the soleus muscle; HYPER exhibited left ventricular hypertrophy and higher citrate synthase activity in the soleus muscle (P<0·05 for all effects). The capacity for NO formation was determined in aortic extracts by formation of [ 3 H]-citrulline from [ 3 H]

Thyroid status affects rat liver regeneration after partial hepatectomy by regulating cell cycle and apoptosis.

Abstract: In rats, various growth factors and hormones, as well as partial hepatectomy (PH) are able to trigger the proliferative response of hepatocytes. Although recent evidence highlights the important role of thyroid hormones and thyroid status in regulating the growth of liver cells in vitro and in vivo models, the mechanism involved in the pro-proliferative effects of thyroid hormones is still unclear. Here we have investigated how in rats made hypo- and hyperthyroid after prolonged treatment respectively with propylthiouracil (PTU) and triiodothyronine (T3), the thyroid status affects liver regeneration after PH by regulating cell cycle and apoptosis proteins. Our results show that both in control and partially hepatectomized animals hyperthyroidism increases the cyclin D1, E and A levels and the activity of cyclin-cdk complexes, and decreases the levels of cdk inhibitors such as p16 and p27. On the contrary hypothyroidism induces a down-regulation of the activity of cyclin cdk complexes decreasing cyclin levels. Thyroid hormones control also p53 and p73, two proteins involved in apoptosis and growth arrest which are induced by PH. In particular, hypothyroidism increases and T3 treatment decreases p73 levels. The analysis of the phosphorylated forms of p42/44 and p38 MAPK revealed that they are induced during hepatic regeneration in euthyroid and hyperthyroid rats whereas they are negatively regulated in hypothyroid rats. In conclusion our data demonstrate that thyroid status can affects liver regeneration, altering the expression and the activity of the proteins involved in the control of cell cycle and growth arrest.

Comparison of potential protective effects of melatonin, indole‐3‐propionic acid, and propylthiouracil against lipid peroxidation caused by potassium bromate in the thyroid gland

Abstract: Potassium bromate (KBrO3) is a prooxidant and carcinogen, inducing thyroid tumors. Melatonin and indole-3-propionic acid (IPA) are effective antioxidants. Some antioxidative effects of propylothiouracil (PTU)—a thyrostatic drug—have been found. The aim of the study was to compare protective effects of melatonin, IPA, and PTU against lipid peroxidation in the thyroids, collected from rats treated with KBrO3, and in homogenates of porcine thyroids, incubated in the presence of KBrO3. Wistar rats were administered KBrO3 (110 mg/kg b.w., i.p., on the 10th day of the experiment) and/or melatonin, or IPA (0.0645 mmol/kg b.w., i.p., twice daily, for 10 days), or PTU (0.025% solution in drinking water, for 10 days). Homogenates of porcine thyroids were incubated for 30 min in the presence of KBrO3 (5 mM) plus one of the antioxidants: melatonin (0.01, 0.1, 0.5, 1.0, 5.0, 7.5 mM), or IPA (0.01, 0.1, 0.5, 1.0, 5.0, 7.5, 10.0 mM), or PTU (0.01, 0.1, 0.5, 1.0, 5.0, 7.5, 10.0 mM). The level of lipid peroxidation products (MDA + 4-HDA) was measured spectrophotometrically in thyroid homogenates. In vivo pretreatment with either melatonin or with IPA or with PTU decreased lipid peroxidation caused by KBrO3—injections in rat thyroid gland. Under in vitro conditions, PTU (5.0, 7.5, and 10.0 mM), but neither melatonin nor IPA, reduced KBrO3-related lipid peroxidation in the homogenates of porcine thyroids. In conclusion, melatonin and IPA may be of great value as protective agents under conditions of exposure to KBrO3. © 2005 Wiley-Liss, Inc.

High pre-therapy [99mTc]pertechnetate thyroid uptake, thyroid size and thyrostatic drugs: predictive factors of failure in [131I]iodide therapy in Graves' disease.

Abstract: Background and objective Several factors may interfere with the success rate of radioiodine therapy (RIT) in Graves' disease. Our aim was to evaluate, retrospectively, some of these factors in the outcome of RIT. Methods Patient gender, age at diagnosis, ophthalmopathy, disease duration, thyroid size, drug used as clinical treatment, thionamide withdrawal period during RIT preparation, FT 4 , TSH and [ 9 9 m Tc]pertechnetate thyroid uptake prior to RIT were studied as potential interference factors for RIT success. Eighty-two Graves' disease patients were submitted to RIT after thionamide treatment failure. Prior to RIT, 67 patients were receiving methimazole and 15 propylthiouracil. Thirty-three patients received thionamides during RIT; in 49 patients the medication was withdrawn for 2-30 days. [ 9 9 m Tc]pertechnetate thyroid uptake was determined before RIT. Fixed doses of 370 MBq of [ 1 3 1 I]iodide were administered to all patients. Results Eleven patients became euthyroid; 40 became hypothyroid and 31 remained hyperthyroid. There was no association between outcome and age at diagnosis, gender, ophthalmopathy, pre-RIT FT 4 , TSH, antithyroid antibodies or thyrostatic drug. Multiple logistic regression showed higher probability of treatment success in patients with thyroid mass <53g (odds ratio (OR)=8.9), with pre-RIT thyroid uptake <12.5% (OR=4.1) and in patients who withdrew thionamide before RIT (OR=4.9). Conclusions Fixed doses of 370 MBq of radioiodine seem to be practical and effective for treating Graves' disease patients with [ 9 9 m Tc]pertechnetate uptake <12.5% and thyroid mass <53g. This treatment is clearly not recommended for patients with large goitre. In contrast to what could be expected, patients with a high pre-RIT thyroid uptake presented a higher rate of RIT failure.

Thyroid disease in pregnancy and childhood.

Abstract: The subject of thyroid disease in pregnancy is receiving increasing attention from many scientific disciplines. Thyroid function in pregnancy is characterised by a T4 surge at 12 weeks declining thereafter. Serum thyroid hormone concentrations fall in the second half of pregnancy but there are few data on normal reference ranges. Fetal brain development depends on T4 transport into the fetus which in turn depends on sufficient maternal iodine supply. There is current concern that adequate iodisation is not present in large parts of Europe. There is increasing evidence that thyroid autoimmunity is associated with fetal loss but the mechanism is unclear and therapy requires carefully conducted studies. While hyperthyroidism in pregnancy is uncommon, effects on both mother and child are critical if untreated. The use of propylthiouracil is recommended together with measurement of TSH receptor antibodies at 36 weeks gestation. Women receiving thyroxine therapy for hypothyroidism or as suppressive therapy should have their dose increased by up to 50% during pregnancy. There are now substantial data to show deleterious effects on child IQ resulting from low maternal T4 (or high TSH) during gestation. Major advances in molecular biology have contributed to elucidation of many genetic causes of congenital hypothyroidism. However, the aetiology of the majority of cases is still unclear and further research is required. The presence of TPO antibodies in about 10% of pregnant women in early gestation is a predictor of an increased incidence of subclinical hypothyroidism during pregnancy and also of postpartum thyroid dysfunction. The latter condition occurs in 5-9% of women and 25-30% progress to permanent hypothyroidism. This review suggests that screening for thyroid function in early pregnancy and levothyroxine intervention therapy for maternal subclinical hypothyroidism should be considered but evidence is awaited. Screening for both thyroid dysfunction and thyroid antibodies ideally at a preconception clinic but certainly in early gestation is recommended.

Dronedarone Administration Prevents Body Weight Gain and Increases Tolerance of the Heart to Ischemic Stress: A Possible Involvement of Thyroid Hormone Receptor α1

Abstract: Hypothyroid heart displays a phenotype of cardioprotection against ischemia and this study investigated whether administration of dronedarone, an amiodarone-like compound that has been shown to preferentially antagonize thyroid hormone binding to thyroid hormone receptor alpha1 (TRalpha1), results in a similar effect. Dronedarone was given in Wistar rats (90 mg/kg, once daily (od) for 2 weeks) (DRON), while untreated animals served as controls (CONT). Hypothyroidism (HYPO) was induced by propylthiouracil administration. Isolated rat hearts were perfused in Langendorff mode and subjected to 20 minutes of zero-flow global ischemia (I) followed by 45 minutes of reperfusion (R). 3,5,3' Triiodothyronine remained unchanged while body weight and food intake were reduced. alpha-Myosin heavy chain (alpha-MHC) decreased in DRON while beta-myosin heavy chain (beta-MHC) and sarcoplasmic reticulum Ca2+ adenosine triphosphatase (ATPase) expression (SERCA) was similar to CONT. In HYPO, alpha-MHC and SERCA were decreased while beta-MHC was increased. Myocardial glycogen content was increased in both DRON and HYPO. In DRON, resting heart rate and contractility were reduced and ischemic contracture was significantly suppressed while postischemic left ventricular end-diastolic pressure and lactate dehydrogenase release (IU/L min) after I/R were significantly decreased. In conclusion, dronedarone treatment results in cardioprotection by selectively mimicking hypothyroidism. This is accompanied by a reduction in body weight because of the suppression of food intake. TRs might prove novel pharmacologic targets for the treatment of cardiovascular illnesses.

Changes in antioxidant status, protein concentration, acetylcholinesterase, (Na+,K+)-, and Mg2+ -ATPase activities in the brain of hyper- and hypothyroid adult rats.

Abstract: It is a common knowledge that metabolic reactions increase in hyperthyroidism and decrease in hypothyroidism. The aim of this work was to investigate how the metabolic reactions could affect the total antioxidant status (TAS), protein concentration (PC) and the activities of acetylcholinesterase (AChE), (Na+,K+)-ATPase and Mg2+ -ATPase in the brain of hyper- and hypothyroid adult male rats. Hyperthyroidism was induced in rats by subcutaneous administration of thyroxine (25 microg/l00 g body weight) once daily for 14 days, while hypothyroidism was induced by oral administration of propylthiouracil (0.05%) for 21 days. TAS, PC, and enzyme activities were evaluated spectrophotometrically in the homogenated brain of each animal. TAS, PC, and Mg2+ -ATPase activity were found unaffected in hyperthyroidism, while AChE and Na+,K+ -ATPase activities were reduced by 25% (p < 0.01). In contrast, TAS, (Na+,K+)-ATPase and Mg2+-ATPase activities were found to be increased (approx. 23-30%, p < 0.001) in the hypothyroid brain, while AChE activity and PC were shown to be inhibited (approx. 23-30%, p < 0.001). These changes on brain enzyme activities may reflect the different metabolic effects of hyper- and hypothyroidism. Such changes of the enzyme activities may differentially modulate the brain intracellular Mg2+, neural excitability, as well as the uptake and release of biogenic amines.

Necrotizing glomerulonephritis and pulmonary hemorrhage associated with carbimazole therapy.

Abstract: Methimazole, carbimazole, and propylthiouracil (PTU) are the mainstays of antithyroid drug therapy. Adverse effects of these drugs have been documented in less than 15% of patients undergoing treatment for hyperthyroidism. Common problems include fever, skin rash, urticaria, arthralgias, and arthritis. Vasculitis associated with antineutrophil anticytoplasmic antibodies (ANCA) has been reported on several occasions following treatment with PTU. However, vasculitis rarely appears to be associated with carbimazole. We report the clinical history of a woman with a necrotizing glomerulonephritis and pulmonary hemorrhage associated with carbimazole therapy.

Evaluation of mechanisms inducing thyroid toxicity and the ability of the enhanced OECD Test Guideline 407 to detect these changes.

Abstract: The OECD has developed an "enhanced Test Guideline 407" (TG 407) protocol for detecting endocrine effects during the course of a 28-day testing scheme. This protocol has gone through a validation process with (anti)estrogenic and (anti)androgenic compounds and substances that affect the thyroid (thyroxine and propylthiouracil). This review investigates whether a 28-day testing scheme would show up alterations in the thyroid-related parameters of the "enhanced TG 407" (T3, T4, TSH, thyroid weight and histopathology), irrespective of the mode of action. For each mode of action, a generally accepted reference chemical was selected and an in-depth literature survey was carried out, and the chemical was evaluated for treatment-related changes of thyroid-dependent parameters. The following model chemicals were selected: ion perchlorate, blockage of iodine uptake; propylthiouracil, inhibition of thyroid hormone synthesis; excess of iodine, blockage of thyroid hormone release; pyrazole, thyroid cytotoxicity; minocycline, thyroid pigmentation; amiodarone, inhibition of TSH synthesis; diethylstilbestrol, competition for thyroid hormone binding globulin; selenium-deficient diet, inhibition of thyroxine deiodination; FDC cadmium, lipid peroxidation; phenobarbital, increase in thyroxine conjugation and biliary excretion; temelastine, thyroxine accumulation. Test data for treatments lasting approximately one month were available for most of these model chemicals, and these demonstrated the expected thyroid-related changes. Thus, it can be concluded that a 28-day testing scheme allows for the detection of thyroid-disrupting chemicals. The literature data also were evaluated according to whether preference can be given to any of the thyroid-related parameters (thyroid/pituitary hormones, thyroid weight and histopathology) with regard to dose-related sensitivities. Due to different study designs (such as treatment duration, application mode, dose selection and parameters used), no clear picture emerged. Therefore, consideration should be given to all of these parameters, which should also help to define the mode of action. Overall, this literature review provides support for the contention that the newly developed "enhanced TG 407" test protocol is well suited to the detection of chemicals that affect the thyroid gland.

Sympathetic nervous system activity in rat thyroid: potential role in goitrogenesis.

Abstract: The role of sympathetic innervation in regulation of thyroid function is incompletely understood. We, therefore, carried out studies in rats utilizing techniques of norepinephrine turnover to assess thyroid sympathetic activity in vivo. Thyroidal sympathetic activity was increased 95% by exposure to cold (4 degrees C), 42% by chronic ingestion of an iodine-deficient diet, and 32% in rats fed a goitrogenic diet (low-iodine diet supplemented with propylthiouracil). In addition, fasting for 2 days reduced sympathetic nervous system activity in thyroid by 38%. Thyroid growth and 125I uptake were also compared in intact and decentralized hemithyroids obtained from animals subjected to unilateral superior cervical ganglion decentralization. Unilateral superior cervical ganglion decentralization led to a reduction in thyroid weight, in 125I uptake by thyroid tissue, and in TSH-induced stimulation of 125I uptake in decentralized hemithyroids. These results suggest that sympathetic activity in thyroid contributes to gland enlargement and may modulate tissue responsiveness to TSH.

Molecular characterization of thyroid toxicity: anchoring gene expression profiles to biochemical and pathologic end points.

Abstract: Organic iodides have been shown to induce thyroid hypertrophy and increase alterations in colloid in rats, although the mechanism involved in this toxicity is unclear. To evaluate the effect that free iodide has on thyroid toxicity, we exposed rats for 2 weeks by daily gavage to sodium iodide (NaI). To compare the effects of compounds with alternative mechanisms (increased thyroid hormone metabolism and decreased thyroid hormone synthesis, respectively), we also examined phenobarbital (PB) and propylthiouracil (PTU) as model thyroid toxicants. Follicular cell hypertrophy and pale-staining colloid were present in thyroid glands from PB-treated rats, and more severe hypertrophy/colloid changes along with diffuse hyperplasia were present in thyroid glands from PTU-treated rats. In PB- and PTU-treated rats, thyroid-stimulating hormone (TSH) levels were significantly elevated, and both thyroxine and triiodothyronine hormone levels were significantly decreased. PB induced hepatic uridine diphosphate-glucuronyltransferase (UDPGT) activity almost 2-fold, whereas PTU reduced hepatic 5 -deiodinase I (5 -DI) activity to < 10% of control in support of previous reports regarding the mechanism of action of each chemical. NaI also significantly altered liver weights and UDPGT activity but did not affect thyroid hormone levels or thyroid pathology. Thyroid gene expression analyses using Affymetrix U34A GeneChips, a regularized t-test, and Gene Map Annotator and Pathway Profiler demonstrated significant changes in rhodopsin-like G-protein-coupled receptor transcripts from all chemicals tested. NaI demonstrated dose-dependent changes in multiple oxidative stress-related genes, as also determined by principal component and linear regression analyses. Differential transcript profiles, possibly relevant to rodent follicular cell tumor outcomes, were observed in rats exposed to PB and PTU, including genes involved in Wnt signaling and ribosomal protein expression.

Short-term thyroxine administration leads to lipid peroxidation in renal and testicular tissues of rats with hypothyroidism

Abstract: Thyroid dysfunction brings about pathological changes in different organs of the body. The aim of the present study was to examine how experimental hypothyroidism and additional short-term high-dose thyroxine administration (one-week) affected lipid peroxidation in renal and testicular tissues of rats. The study was carried out on 30 male Spraque-Dawley rats. The experimental animals were divided into 3 groups as control, hypothyroidism and hypothyroidism + thyroxine administration. Both malondialdehyde (MDA) and glutathione (GSH) levels were lower in renal and testicular tissues of the hypothyroidism group than the control and hypothyroidism + thyroxine administration groups and the levels in hypothyroidism + thyroxine administration group were higher than those in the control and hypothyroidism groups (p < 0.001). Results of the study demonstrate that hypothyroidism reduced oxidant stress in kidney and testis tissues, but short-term, high-dose thyroxine administration in addition to hypothyroidism increased oxidant stress in the same tissues of rats.

Fulminant hepatic failure associated with propylthiouracil: A case report with treatment emphasis on the use of plasmapheresis

Abstract: Propylthiouracil is a commonly used medication for hyperthyroidism. Though propylthiouracil-induced hepatotoxicity is a rarely encountered problem, death due to fulminant hepatic failure may occur. In the English literature, only 34 cases have been described with severe hepatotoxicity secondary to this drug. Here we report a case of fulminant hepatic failure due to propylthiouracil and review the issues of treatment and management with special emphasis on the use of plasmapheresis in such situations.

An update on the pharmacological management of hyperthyroidism due to Graves' disease.

Abstract: Pharmacological treatment, usually by thionamides (carbimazole, methimazole, propylthiouracil) is, in addition to radioiodine therapy and thyroidectomy, one of the available therapies for Graves' hyperthyroidism. Thionamides represent the treatment of choice in pregnant women, during lactation, in children and adolescents and in preparation for radioiodine therapy or thyroidectomy. Side effects are relatively frequent but are in general mild and transient. Two main regimens are available: titration method (use of the lowest dose maintaining euthyroidism; duration: 12-18 months) and block-and-replace method. Neither one has clear advantages in terms of outcome but the latter method is associated with more frequent side effects. Hyperthyroidism relapses in approximately 50% of patients, to whom ablative therapy should be offered.

Non-Invasive Management of Fetal Goiter during Maternal Treatment of Hyperthyroidism in Grave’s Disease

Abstract: There is an increased risk of fetal goiter in patients who have a history of Grave's disease and undergo propylthiouracil (PTU) treatment during pregnancy. In this report, we describe a case of a fetal goiter detected by antenatal ultrasound at the 26th week of gestation in a mother treated with PTU for Grave's disease. A 32 x 38 x 20 mm fetal goiter was detected, each lobe measured 30 x 18 x 18 mm and estimated volume was 10 cm3. Subsequently, fetal thyroid function was assessed by umbilical fetal blood sampling. Cord blood showed elevated serum TSH (40.2 mU/l) and normal concentrations of free T4 (9.5 pmol/l) and free T3 (2.6 pmol/l). There were no other ultrasonographic signs of fetal hypothyroidism. Based on the above findings, the mother's PTU dosage was reduced to 50 mg daily from a total of 150 mg and weekly ultrasonographic examinations were performed. Six weeks after the initial ultrasound, a complete regression of the fetal goiter was noted. At the 34th week of gestation, the patient was delivered due to intrauterine growth restriction and oligohydramnios and gave birth to a male, weighing 1,920 g. The newborn thyroid was not palpable and thyroid ultrasonography was normal. Cord blood TSH was normal (8.4 mU/l) and free T4 was within lower normal limit (9.03 pmol/l). Ten days later, newborn thyroid function was normal and the baby did well afterwards. In conclusion, after the evaluation of fetal thyroid status, selected cases with fetal goiter can be initially managed without intrauterine treatment.

Inhibition of pituitary type 2 deiodinase by reverse triiodothyronine does not alter thyroxine-induced inhibition of thyrotropin secretion in hypothyroid rats

Abstract: Objectives: Intrapituitary triiodothyronine (T3) production plays a pivotal role in the control of TSH secretion. Its production is increased in the presence of decreased serum thyroxine (T4) concentrations and the enzyme responsible, deiodinase type 2 (D2), is highest in hypothyroidism. In order to document the role of this enzyme in adult rats we developed an experimental model that inhibited this enzyme using the specific inhibitor, reverse T3 (rT3). Methods: Hypothyroidism was induced with propylthiouracil (PTU; 0.025g/l in drinking water) which in addition blocked deiodinase type 1 (D1) activity, responsible for the rapid clearance of rT3 in vivo. During the last 7 days of the experiment, the hypothyroid rats were injected (s.c.) for 4 days with 0.4 or 0.8nmol T4 per 100g body weight (bw) per day. For the last 3 days, the same amount of T4 was infused via s.c. minipumps. In additional groups, 25nmol rT3/100g bw per day were added to the 3-day infusion of T4. Results: Infusion of 0.4nmol T4/100g bw per day did not affect the high serum TSH levels, 0.8nmol T4/100g bw per day decreased them to 57% of the hypothyroid values. The infusions of rT3 inhibited D2 activity in all organs where it was measured: the pituitary, brain cortex and brown adipose tissue (BAT). In the pituitary, the activity was 27%, to less than 15% of the activity in hypothyroidism. Despite that, serum TSH levels did not increase, serum T4 concentrations did not change and the changes in serum T3 were minimal. Conclusions: We conclude that in partly hypothyroid rats, a 3-day inhibition of D2 activity, without concomitant change in serum T4 and minimal changes in serum T3 levels, is not able to upregulate TSH secretion and we postulate that this may be a reflection of absent or only minimal changes in circulating T3 concentrations.

Propylthiouracil attenuates acetaminophen-induced renal damage in the rat.

Abstract: SUMMARY: Background: To date, there is no specific antidote to acetaminophen poisoning. Propylthiouracil (PTU) has been shown to be protective against acetaminophen (APAP)-induced liver damage in rats; however, the nephroprotective effect of propylthiouracil has not been studied yet. Methods: In order to verify this, rats were given different doses of PTU (100, 200 or 400 mg/kg per body weight, orally) 1 h before a nephrotoxic dose of APAP (1000 mg/kg per body weight, intraperitoneally (i.p.)). Results: Propylthiouracil pretreatment significantly reduced APAP-induced nephrotoxicity in a dose-dependant manner, as evidenced by reduction in plasma creatinine and by amelioration of renal pathology (interstitial congestion, tubular cell degeneration and necrosis). Conclusion: The mechanism of protection by PTU is probably not due to the sparing effect of non-protein thiol (approximately 95% of which is reduced glutathione), as similar depletion of renal glutathione was observed regardless of PTU pretreatment; other mechanisms are suggested.

Management of a pregnant patient with Graves' disease complicated by propylthiouracil induced agranulocytosis.

Abstract: Relapse and exacerbation of Graves' disease during pregnancy is rare, and thionamide induced agranulocytosis is an uncommon side effect. We report a case of a pregnant woman in her 24 th week of gestation that experienced a relapse of Graves' disease that was complicated by propylthiouracil induced agranulocytosis. Following the discontinuation of propylthiouracil and administration of a broad-spectrum of antibiotics, agranulocytosis subsided within 10 days. A total thyroidectomy to avoid any future relapse was planned and a short course of a beta-adrenergic blocker and Lugol solution were prescribed before the operation. At the 28th week of gestation, a total thyroidectomy was performed without complications and thyroxine replacement therapy was commenced. At the 40th week of gestation, labor was induced and a 3,370 g healthy male infant was born without clinical features of thyrotoxicosis. We report herein on the patient and the treatment options for this rare and complicated case.

Hyperthyroidism during pregnancy: etiology, diagnosis and management.

Abstract: Pregnancy has marked effects on thyroid physiology and autoimmune thyroid disease tends to ameliorate through gestation due to the general immunosuppression seen in pregnancy. There is a need for trimester-specific thyroid hormone reference ranges. Hyperthyroidism in pregnancy - usually due to Graves' disease - is not common but, if the patient is compliant, a good outcome can be expected for both mother and child if treatment with anti-thyroid drugs (propylthiouracil is preferred) is instituted. Thyroid-stimulating hormone receptor antibody should be measured at 36 weeks in such patients in order to predict the possibility of neonatal hyperthyroidism. Transient gestational hyperthyroidism is often associated with hyperemesis gravidarum and thyroid function should be checked in patients severely affected by this condition. Radioiodine therapy is contraindicated in pregnancy but thyroid surgery may be performed safely in the second trimester. Autoimmune thyroiditis and Graves' hyperthyroidism occur quite commonly in postpartum women.

Leukocytoclastic Vasculitis: A Rare Manifestation of Propylthiouracil Hypersensitivity

Abstract: Objective: We report a case of leukocytoclastic vasculitis as a manifestation of propylthiouracil hypersensitivity. Clinical Presentation and Intervention: A 66-year-old woman with a history of a toxic adenoma was referred for evaluation of a purpuric rash on the legs and buttocks bilaterally. She was biochemically hyperthyroid. Biopsy of the skin lesions revealed leukocytoclastic vasculitis. Propylthiouracil therapy was discontinued, and methimazole started. The purpuric rash resolved and surgical treatment for toxic adenoma resulted in euthyroid state. Conclusion: This report indicated that leukocytoclastic vasculitis should be considered in the differential diagnosis of patients with a vasculitic rash. The discontinuation of the propylthiouracil was associated with disappearance of the lesions.

On association between cortical 5-HT2A receptors and behavior in rats with experimental thyroid disturbances.

Abstract: Thyroid hormones (TH) were hypothesized to affect behavior via neurotransmission alterations. The present study was aimed to reveal effects of chronic TH deficit and excess on some types of adaptive behavior (catalepsy, acoustic startle reflex, open-field performance), sexual arousal and cerebral 5-HT2A serotonin receptors of adult Wistar rats. Administration of thyroxine synthesis inhibitor, propylthiouracil (PTU, 50 mg/l, 28 days), in drinking water produced substantial decrease in plasma thyroxine level and body weight gain, attenuated significantly acoustic startle reflex amplitude, sexual motivation and plasma testosterone surge in response to receptive female introduction, increased predisposition to catalepsy without considerable effects on open-field performance. l -thyroxine treatment (T4, 0,5 mg/l, 28 days) caused significant plasma thyroxine augmentation, somatic growth retardation and disturbances in sexual but not in other types of behavior studied. TH dysfunctions markedly increased number of DOI-induced wet dog shakes reflecting high functional activity of 5-HT2A receptors without any effect on cortical 5-HT2A receptor mRNA level. The involvement of cerebral 5-HT2A receptors alterations at posttranslational level in mechanisms of TH effects on sexual arousal was suggested. The data attract particular attention to undesirable effects of PTU and l -thyroxine treatment on behavior.

Effects of maternal hyperthyroidism and antithyroid drug therapy on congenital malformation of newborn infants

Abstract: Objective To evaluate the relationship between the incidence of congenital malformations of newborns and maternal hyperthyroidism with antithyroid drug (ATD) therapy during pregnancy.Methods The clinical data of 100 cases of pregnant women with hyperthyroidism and their 101 offsprings born in Peking Union Medical College Hospital during 1983-2003 were analyzed retrospectively. According to the maternal thyroid function, and antithyroid drugs taken during the first trimester of pregnancy, subjects were divided into different groups. The incidence of congenital malformations of newborns and risk factors, especially the effects of maternal hyperthyroidism with antithyroid drug therapy were analysed.Results The prevalence of congenital malformation in infants born to mothers who had hyperthyroidism during pregnancy (6.9%, 7/101) was significantly higher than that of all the infants born in the same hospital during the same period (0.9%, 212/22 765, P 0.01). The difference of the incidence of malformed infants born to mothers with hyperthyroidism (9.6%, 5/52) or euthyroidism (4.1%, 2/49) during the first trimester was not significant ( P 0.05). The incidence of malformed infants whose mothers received methimazole (MMI; 41.7%, 5/12)was significantly higher than that of mothers treated with propylthiouracil (PTU)(3.6%,1/28) and without ATDs(1.6%,1/61) , respectively ( P 0.01). The Loglinear model analyses showed that mothers receiving MMI during the first trimester of pregnancy was independent risk factor for the increased incidence of malformation of their infants (L.R. square= 15.668, P =0.0003). Conclusions The risk of congenital malformation in infants whose mothers take MMI during the first trimester may be increased. Therefore, we suggest that MMI should not be used as a choice of drug in treatment of pregnant women with hyperthyroidism.