Showing papers on "Propylthiouracil published in 2002"

High Dose 131I Therapy for the Treatment of Hyperthyroidism Caused by Graves’ Disease

Abstract: Radioactive iodine (131I) has become the most widely used therapy for patients with hyperthyroidism caused by Graves’ disease in the United States. There remains, however, significant variability among 131I dosing regimens, and it is clear that most patients ultimately develop hypothyroidism after therapy. To avoid persistent hyperthyroidism, we adopted a high dose 131I therapy protocol based on measurement of 24-h thyroid 123I uptake designed to deliver 8 mCi (296 MBq) to the thyroid gland 24 h after 131I administration. To evaluate the efficacy of this protocol, we reviewed our clinical experience over a 7-yr period. We treated 261 patients (219 women and 42 men) with hyperthyroidism caused by Graves’ disease with 131I [mean dose, 14.6 mCi (540 MBq)] between 1993 and 1999. Before treatment, 207 (79%) had received an antithyroid drug (109 propylthiouracil and 98 methimazole). We determined their thyroid status 1 yr after treatment in relation to age, pretreatment with an antithyroid drug, pretreatment th...

Teratogen update: antithyroid drugs—methimazole, carbimazole, and propylthiouracil

Abstract: Thyrotoxicosis occurs in about 0.2% of pregnancies and is caused most frequently by Graves disease (Burrow, ’85; Kriplani et al., ’94). Graves disease is an autoimmune disorder characterized by the production of antibodies, immunoglobulins of the IgG class, directed against thyroid stimulating hormone (TSH) receptors (Shoenfeld and Schwartz, ’84). This results in the excess production of thyroid hormones. Because IgG antibodies pass through the human placenta, their transfer can induce stimulation of the fetal thyroid gland causing fetal hyperthyroidism (Hollingsworth, ’83). Thyrotoxic fetuses have a high risk for prematurity, intrauterine growth retardation, craniostenosis, cardiac failure, fetal hydrops, and intrauterine death (Treadwell et al., ’96; Zimmerman, ’99). This is apparently unrelated to the status of maternal thyroid function and effectiveness of treatment (Hollingsworth, ’83; Porreco and Bloch, ’90). Antithyroid drugs, which interfere with the synthesis of thyroid hormones, are the treatment of choice for thyrotoxicosis in pregnancy. Propylthiouracil (PTU), methimazole (MMI) and carbimazole (CMZ) are thioureylenes, which belong to the family of thioamides. The antithyroid compounds currently used in the United States are PTU and MMI. In the United Kingdom and Europe, CMZ, a carboxy derivative of MMI, is available, and its antithyroid action is due to its conversion to MMI after absorption. Although both PTU and MMI cross the placenta, MMI was originally reported to have a three times greater placental transfer than PTU (Marchant et al., ’77). PTU is therefore preferred over MMI because of its lower transplacental passage (Farwell and Braverman, ’96). It was recently suggested, however, that both drugs have similar kinetics of placental transfer (Mortimer et al., ’97). All antithyroid drugs may inhibit fetal thyroid function causing fetal hypothyroidism. This is usually transient with a return to the euthyroid state within several days or weeks after birth. (Kriplani et al., ’94; Wing et al., ’94; Vanderpump et al., ’96;). For that reason, and because of the transplacental passage of maternal antithyroid antibodies, it may be important to assess fetal thyroid function in treated mothers with Graves disease either by Doppler echography or, in selected cases, by fetal blood sampling (Porreco and Bloch, ’90; Lutton et al., ’97). Fetal hyperthyroidism can be treated by administration of PTU to the mother (Wallace et al., ’95; Treadwell et al., ’96). Infants of mothers with Graves disease who had been treated with antithyroid drugs may have hypothyroidism (due to drug transfer) or hyperthyroidism (due to the transfer of antibodies). It is therefore important to assess the thyroid function of each neonate born to a treated hyperthyroid mother, especially if thyroid enlargement is observed by ultrasonography (Brunner and Dellinger, ’97; Momotani et al., ’97; Zimmerman, ’99). This update will review the use of antithyroid drugs during pregnancy addressing the risk of congenital anomalies. Special attention will be given to the possible associations between in utero exposure to MMI and aplasia cutis congenita and a spectrum of congenital anomalies including choanal atresia. The risk of fetal goiter after treatment with all antithyroid drugs, and possible neurodevelopmental toxicity will also be discussed.

Are the effects of T3 on resting metabolic rate in euthyroid rats entirely caused by T3 itself

Abstract: Because we previously reported that T3 and 3,5-diiodo-l- thyronine (3,5-T2) both increase resting metabolic rate (RMR), 3,5-T2 could be another thyroidal regulator of energy metabolism. This effect of 3,5-T2 is evident in rats made hypothyroid by propylthiouracil and iopanoic acid, not in normal euthyroid (N) rats. Possibly, under euthyroid conditions, active 3,5-T2 may need to be formed intracellularly from a precursor such as T3. We tested this hypothesis by giving a single injection of T3 to N rats and comparing the time course of the variations in RMR with those of the changes in the serum and hepatic levels of 3,5-T2. Acute injection had an evident effect on RMR, 25 h earlier, in N rats than in rats made hypothyroid by propylthiouracil and iopanoic acid, maximal values (+40%) being reached in the former at 24–26 h. In N rats, the simultaneous injection of actinomycin D with the T3 inhibited the late part of the effect (after 24 h) more strongly than the early part (14–24 h). In serum and liver, 3,5-T...

Bone remodelling markers and serum cytokines in patients with hyperthyroidism

Abstract: Summary objective This study was designed in order to evaluate bone turnover with bone formation and resorption markers in hyperthyroidism and its possible relationship with serum cytokines interleukin 6 (IL-6) and tumour necrosis-α (TNF-α), levels of thyroid hormones and thyroid autoantibodies. design and patients Twenty-six hyperthyroid patients including nine with Graves’ disease, 14 with toxic multi-nodular disease and three toxic adenoma were studied. Twenty normal subjects served as the control group. measurements Serum calcium, phosphorus, total and bone-specific alkaline phosphatase, procollagen type 1-C peptide (PICP), osteocalcin, IL-6 and TNF-α measurements were performed and deoxypyridinoline (free DPD), calcium, phosphorus and creatinine levels were measured in fasting morning urine specimens of all hyperthyroid patients and all controls. Also, serum total and free T3 and T4 and TSH were analysed and thyroid antiperoxidase and antithyroglobulin antibodies were determined in sera of hyperthyroid patients. Patients with hyperthyroidism received propylthiouracil treatment until the achivement of euthyroidism and then serum cytokine levels were remeasured. results Mean serum values of osteocalcin, total and bone-specific alkaline phosphatase were all significantly higher in hyperthyroid patients than in normal controls. PICP levels were not significantly different between these two groups. Urinary deoxypyridinoline levels were markedly elevated in hyperthyroid patients compared to the control group. There was a significant positive correlation between urinary free DPD levels and serum free T3, free T4 and T4 levels. Serum free T4 levels also correlated with urinary calcium levels. Serum IL-6 values were significantly higher in hyperthyroid patients compared to control group. TNF-α levels were slightly lower in patients with hyperthyroidism. No significant correlation was found between bone remodelling markers and serum cytokines. Serum Il-6 levels were correlated positively with age. After the treatment period both IL-6 and TNF-α returned to levels comparable with euthyroid controls. conclusion Bone turnover is increased in favour of resorption and the rate of resorption is associated with the levels of thyroid hormones in hyperthyroidism. The increase in the levels of serum IL-6 in hyperthyroidism is not related directly with bone resorption seen in hyperthyroidism.

Steroid Receptor Coactivator-1 Deficiency Causes Variable Alterations in the Modulation of T3-Regulated Transcription of Genes in Vivo

Abstract: Thyroid hormone exerts its biological effect by binding to a TR. Both liganded and unliganded TRs regulate the transcription of T3-responsive genes. Cofactors with activating or repressing function modulate the transcriptional regulation by TRs. We showed that steroid receptor coactivator 1 (SRC-1)-deficient mice (SRC-1−/−) exhibit partial resistance to thyroid hormone at the level of the pituitary thyrotrophs. To determine whether SRC-1 deficiency affects globally T3-dependent transcriptional regulation, we studied the effects of thyroid hormone deprivation and replacement on the expression of several genes in different tissues of SRC-1−/− and wild-type mice (SRC-1+/+). Thyroid hormone deficiency was induced by a low iodine diet (LoI) supplemented with propylthiouracil (PTU) for 2 wk. l-T3 was injected ip for the last 4 d in one group (PTU+T3 group), and another group (PTU group) received only vehicle. Levels of mRNAs for T3-responsive genes were determined by Northern blotting: GH and TSHβ in pituitary;...

Thyroid-stimulating hormone in adult euthyroid and hypothyroid horses.

Abstract: The purpose of this study was to validate a thyroid-stimulating hormone (TSH) assay in a model of equine hypothyroidism. Thyrotropin-releasing hormone (TRH) stimulation tests were performed in 12 healthy adult mares and geldings, aged 4 to greater than 20 years, before and during administration of the antithyroid drug propylthiouracil (PTU) for 6 weeks. Serum concentrations of equine TSH, total and free thyroxine (T4), and total and free triiodothyronine (T3) were measured. Before PTU administration, mean ± standard deviation baseline concentrations of TSH were 0.40 ± 0.29 ng/mL. TSH increased in response to TRH, reaching a peak concentration of 0.78 ± 0.28 ng/mL at 45 minutes. Total and free T4 increased from 12.9 ± 5.6 nmol/L and 12.2 ± 3.5 pmol/L to 36.8 ± 11.4 nmol/L and 23.1 ± 5.9 pmol/L, respectively, peaking at 4–6 hours. Total and free T3 increased from 0.99 ± 0.51 nmol/L and 2.07 ± 1.14 pmol/L to 2.23 ± 0.60 nmol/L and 5.78 ± 1.94 pmol/L, respectively, peaking at 2–4 hours. Weekly measurements of baseline TSH and thyroid hormones during PTU administration showed that total and free T3 concentrations fell abruptly and remained low throughout PTU administration. Total and free T4 concentrations did not decrease dramatically until weeks 5 and 4 of PTU administration, respectively. A steady increase in TSH concentration occurred throughout PTU administration, with TSH becoming markedly increased by weeks 5 and 6 (1.46 ± 0.94 ng/mL at 6 weeks). During weeks 5 and 6 of PTU administration, TSH response to TRH was exaggerated, and thyroid hormone response was blunted. Results of this study show that measurement of equine TSH in conjunction with thyroid hormone measurement differentiated normal and hypothyroid horses in this model of equine hypothyroidism.

Expression of 5'-deiodinase enzymes in normal pituitaries and in various human pituitary adenomas

Abstract: Objective: Local 5 0 -deiodination of L-thyroxine (T4) to active thyroid hormone 3,3 0 ,5-tri-iodothyronine (T3) catalyzed by the two 5 0 -deiodinase enzymes (D1 and D2) regulates various T3-dependent functions in the anterior pituitary and has been well studied in rodents. Only limited information about deiodinase expression and its cellular distribution in human anterior pituitaries is available. Design: We examined 5 0 -deiodinase enzyme activities in pituitary adenomas (18 non-functioning, seven TSH-producing, one GH- and TSH-producing, five GH-producing, eight prolactin (PRL)-producing, two adenomas each from patients with Cushing’s disease and Nelson’s syndrome) and three normal anterior pituitaries. Methods: Activities were measured as release of 125 I 2 from tyrosyl-ring labeled reverse T3 with or without propylthiouracil, a potent inhibitor of D1 which does not influence D2 activities. Results: Most of the adenomas and normal tissues expressed both isoenzymes, with D2 activity higher than D1. In a few tissues D1 activity was higher than D2 and some tissues did not express D1 activity at all. Highest activities of both enzymes were found in TSH- and PRL-producing adenomas but absolute activities and the D1/D2 ratio were variable in the same kind of tumor in different patients. Conclusion: The finding that all examined tissues expressed 5 0 -deiodinase activity, most of them expressing both isoenzymes, implies that both enzymes are still active in tumors and that local deiodination is important for the function and feedback regulation of human anterior pituitary.

Retrospective analysis of 18 cases of antithyroid drug (ATD)-induced agranulocytosis.

Abstract: In this study, we retrospectively analyzed 18 patients in whom antithyroid drug (ATD)-induced agranulocytosis developed during treatment of Graves' disease. All patients were more than 20 years of age, and we saw no correlation between age and the development of agranulocytosis. In 17 of 18 patients, ATD-induced agranulocytosis developed within 2 to 12 weeks of starting ATD treatment. Development of agranulocytosis was related to the dose of ATD. In some patients, agranulocytosis developed abruptly, and even weekly routine WBC and granulocyte counts failed to predict all case occurrences. Fever and sore throat were the earliest symptoms of agranulocytosis; patients who developed either of these symptoms were closely monitored immediately with WBC and granulocyte count examinations. In this series of patients, treatment with granulocyte-macrophage colony stimulating factor (GM-CSF) increased the granulocyte counts, whereas the effectiveness of glucocorticoid treatment was not confirmed.

Clinical Features and Outcomes in Children with Antineutrophil Cytoplasmic Autoantibody–Positive Glomerulonephritis Associated with Propylthiouracil Treatment

Abstract: A retrospective investigation was conducted by members of the Japanese Society for Pediatric Nephrology from 1990 to 1997 to define the clinical features and outcomes in children with antineutrophil cytoplasmic autoantibody (ANCA)-positive glomerulonephritis associated with propylthiouracil treatment. Seven Japanese pediatric patients who had myeloperoxidase-specific ANCA-positive biopsy-proven pauci-immune necrotizing crescentic glomerulonephritis associated with propylthiouracil administration were entered in the study. Three patients had nephritis alone, and four had nephritis and extrarenal organ system vasculitis. Females predominated, and the mean age at onset was 14 yr. Propylthiouracil was reduced or discontinued in all patients and was switched to methimazole in three patients. For the treatment of nephritis, five patients received corticosteroids; three had pulse methylprednisolone, one had plasma exchange, and one had plasma exchange and pulse methylprednisolone before initiating oral prednisolone. The remaining two patients received cyclophosphamide and corticosteroids, one of whom had pulse methylprednisolone before initiating oral prednisolone and cyclophosphamide. All patients achieved remission. In general, ANCA titers correlated with the response to treatment and disease activity, with some exceptions. No patient progressed to end-stage renal disease, renal dysfunction, or death during the follow-up period (58 +/- 25 mo; range, 32 to 108 mo). All but one patient remained euthyroid. In conclusion, this experience suggests that the clinical disease spectrum of ANCA-positive disease associated with propylthiouracil treatment is similar in pediatric and adult patients and that the overall prognosis may be better than that in the non-drug-induced ANCA-positive disease.

Methimazole-induced antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis and lupus-like syndrome with a cutaneous feature of vesiculo-bullous systemic lupus erythematosus.

Abstract: Sir, It has been reported that lupus erythematosus (LE)-like adverse reaction is induced by various drugs, e.g. procainamide, hydralazine, isoniazid and diphenylhydantoin (1, 2). Antithyroid agents can also induce this syndrome. Propylthiouraci l has been reported to induce perinuclear antineutrophil cytoplasmic antibody (MPO-ANCA)positive vasculitis (3, 4). Methimazole and carbimazole, two other antithyroid drugs classiŽ ed with propylthiouracil as thionamides, can also cause ANCA-positive vasculitis, but much less frequently than propylthiouracil (4, 5). Other adverse eVects related to methimazole include fever, rash, arthralgia, hepatitis, agranulocytosis and lupus-like syndrome (4, 6). However, only a few reports have described the skin symptoms and the Fig. 1. Vesicles (arrows) and crusts are present on the lower leg. histological Ž ndings in detail in antithyroid agentinduced lupus-like syndrome. We report on a patient 62% segmental neutrophils and 1% eosinophils, a platelet with Graves’ disease who, after being treated with count of 470 109/l, a hemoglobin level of 6mg/dl, a reticulocyte count of 4.4%, a mean corpuscular volume of 87.6  , methimazole for one week, developed a blistering erupprothrombin time 9 s (control 10 s) and activated partial tion on the hands and legs. To our knowledge, this is thromboplastin time 25 s (control 30 sec). Urinalysis was the Ž rst report describing methimazole-induced lupusunremarkable. A chest X-ray Ž lm showed a bilateral, groundlike syndrome and ANCA-positive vasculitis with a glass appearance. Treatment with blood components and cutaneous feature of vesiculo-bullous systemic lupus methylprednisolone was given. Owing to persistent respiratory insuYciency, the patient was intubated. A skin biopsy specimen erythematosus (SLE). from the lower leg revealed a neutrophilic inŽ ltrate with nuclear dusts in the dermal papillae and tips of rete ridges, and vacuolar degeneration at the basement membrane zone CASE REPORT with subepidermal blister formation (Fig. 2). Direct immunoAn 18-year-old female with a 2-year history of hyperthyroid uorescence study showed linear deposition of IgG and IgA ism, which was treated with a 6-month course of propylthiouraat the basement membrane zone (Fig. 3). The indirect cil and propranolol, had discontinued the medications for one immuno uorescence study was negative. An open lung biopsy year until the recurrence of hyperthyroidism presented as specimen revealed an intra-alveolar hemorrhage and capillartremor, palpitation and heat intolerance. The patient did not itis, as suggested by focally expanded and disrupted alveolar have a history of systemic rheumatic disease or any previous septa replaced by a neutophilic inŽ ltrate. Further investigation complaint of photosensitivity and Raynaud phenomenon. The revealed PR3-ANCA (enzyme immunoassay, Pharmacia laboratory studies revealed the anti-thyroglobulin antibody Diagnostics GmbH & C. KG, Freiburg, Germany) 4 EU/ml (particle agglutination method, Fujirebio Co., Japan) level (normal <7),MPO-ANCA (enzyme immunoassay, Pharmacia 1:25,600 (normal <1:80), anti-microsomal antibody (particle Diagnostics) 62 EU/ml (normal < 7), C3 35.7mg/dl (normal agglutination method) 1:10,240 (normal <1:80), free T4 81.61–118.41 ) and C4 6.5mg/dl (normal 27.45 ± 10.72). 0.53 ng/dl (normal 0.6–1.6), and TSH 0.27 mU/ml (normal Antinuclear antibody of speckled type was found at a serum <6.5). She was then treated with methimazole 15mg and dilution of 1:80 by means of indirect immuno uorescence propranolol 40mg daily. A week later, hemoptysis, cough, microscopy, using HEP-2 cells (Medical & Biological dyspnea and an itchy skin rash were noted. The skin lesions Laboratories Co., Japan (MBL)). Anti-ds DNA (enzyme consisted predominantly of vesicles 1–3mm in size and crusted immunoassay, MBL) 24.3 IU/ml (normal <12) was also erosions on the legs and dorsa of the hands and feet (Fig. 1). noted. The anti-phospholipid antibody (enzyme immunoassay, The patient was admitted to our hospital where laboratory Diagnostica Stago, France) level was 33.95 IU/ml (normal investigation showed a leukocyte count of 10.1 109/l with <5), but anti-cardiolipin antibody (enzyme immunoassay, Shield Diagnostics Ltd., UK) was negative. The anti-SS-A *Author for correspondence. antibody (double radial immunodiVusion, MBL) was positive,

Comparison of toxicity studies based on the draft protocol for the 'Enhanced OECD Test Guideline no. 407' and the research protocol of 'Pubertal Development and Thyroid Function in Immature Male Rats' with 6-n-propyl-2-thiouracil.

Abstract: Two repeated-dose studies of 6-n-propyl-2-thiouracil (PTU) in male rats based on the research protocol 'Pubertal Development and Thyroid Function in Immature Male Rats' (pubertal assay) proposed by the Endocrine Disrupter Screening and Testing Advisory Committee (EDSTAC) and the draft protocol of the 'Enhanced OECD Test Guideline 407' (enhanced TG 407) were performed to investigate the suitability of both assays as screening methods for the detection of endocrine-mediated effects and to compare their sensitivity for the endocrine-mediated effects. In the pubertal assay, PTU at doses of 0, 0.01, or 1 mg/kg per day was orally administered to male Sprague-Dawley rats for 30 days, starting at 23 days of age. In the enhanced TG 407 the same doses of PTU were orally administered to male Sprague-Dawley rats for 28 days, starting at 7 weeks of age. In the pubertal assay, decreased serum thyroxine (T4) and triiodothyronine (T3), increased thyroid and pituitary weights, hypertrophy of follicular epithelial cells in the thyroid, and increased basophilic cells in the pituitary were detected as endocrine-mediated effects of PTU in the 1 mg/kg group. In the enhanced TG 407, decreased T4 and T3 were detected in both the 0.01 and 1 mg/kg groups, together with increased thyroid-stimulating hormone in the 1 mg/kg group, increased thyroid and pituitary weights in the 1 mg/kg group, and hypertrophy of follicular epithelial cells in the thyroid and increased basophilic cells in the pituitary of the 1 mg/kg group. Thus, among the parameters tested, the thyroid hormone levels, organ weight changes, and the histopathological assessment allowed detection of the endocrine-related effects of PTU in both the pubertal assay and the enhanced TG 407, but the sensitivity of the hormone analysis was higher in the latter.

Anti-neutrophil cytoplasmic autoantibody (ANCA) profiles in propylthiouracil-induced lupus-like manifestations in monozygotic triplets with hyperthyroidism.

Abstract: We describe the ANCA profile of two monozygotic triplets (A and B) treated with propylthiouracil (PTU) for hyperthyroidism who developed LE-like manifestations. Triplet C also developed hyperthyroidism but was not treated with PTU and never experienced LE-like symptoms. Triplet A and B showed a marked rise in P-ANCA titer to 1:1280 after PTU was introduced whereas triplet C never had a titer higher than 1:80. Consecutive sera were investigated for ANCA to six different neutrophil granule proteins. Triplet A and B, but not C, both developed a strongly positive elastase-ANCA. Our results confirm the importance of a genetic factor influencing the susceptibility to drug-induced LE.

Effect of iodine or iopanoic acid on thyroid Ca2+/NADPH-dependent H2O2-generating activity and thyroperoxidase in toxic diffuse goiters.

Abstract: Objective: The aim of the present study was to compare the effects of iopanoic acid (IOP) or a saturated solution of potassium iodide (SSKI) administration to patients with toxic diffuse goiters (TDG). Design: Patients with TDG are treated with thionamides and high doses of iodine preoperatively. In this study, two types of preoperative drug regimens were used: propylthiouracil or methimazole plus SSKI for 10 ‐ 15 daysOna 8U or IOP for 7 daysOna 6U: Methods: Serum thyroid hormones (total and free thyroxine (T4), total tri-iodothyronine (T3) and reverse T3 (rT3), were evaluated after 7 days of either SSKI or IOP treatment, and after 10 ‐ 15 days of SSKI administration. During thyroidectomy, samples of thyroid gland were obtained to evaluate thyroperoxidase and thyroid H2O2-generating activities. Results: Serum total T3 was significantly decreased after 7 days of either treatment, and serum rT3 was significantly increased in IOP-treated patients. Serum total and free T4 were unaffected by 7 days of IOP treatment, but decreased after 7 days of SSKI treatment, although significantly diminished levels were only reached after a further 3 ‐ 8 days of SSKI administration. During both drug regimens, serum TSH remained low (SSKI: 0:159^0:122; IOP: 0:400^0:109mU=ml). Thyroperoxidase activity was significantly lower in thyroid samples from patients treated with SSKI for 10 ‐ 15 days than in the thyroid glands from IOP-treated patients. However, thyroid H2O2 generation was inhibited in samples from patients treated with either IOP or SSKI. Conclusions: We show herein that IOP treatment can be effective in the management of hyperthyroidism and that this drug inhibits thyroid NADPH oxidase activity, just as previously described for SSKI, probably due to its iodine content.

Effect of hypothyroidism on the subcellular distribution of Ca2+/calmodulin-stimulated protein kinase II in chicken brain during posthatch development.

Abstract: In developing chicken brain Ca 2+ /calmodulin-stimulated protein kinase II (CaMPK-II) changes from being primarily cytosolic to being primarily particulate during the protracted maturation period. To investigate whether thyroid hormone levels may be involved in regulating this subcellular redistribution, we raised chickens from 1 day posthatching on food soaked in 0.15% (wt/vol) propylthiouracil (PTU) plus 0.05% (wt/vol) methimazole (MMI). This produced a mild hypothyroidism specifically during the maturation period and resulted in a 67% reduction in the levels of free triiodothyronine (T 3 ) at 42 days. The concentrations of α- and β-CaMPK-II in cytosol (S3) and crude synaptic membrane (P2M) fractions from forebrain were measured by three methods : Ca 2+ /calmodulin- or Zn 2+ -stimulated autophosphorylation or binding of biotinylated calmodulin. By all three methods hypothyroid animals showed a marked retardation of the redistribution of both subunits of CaMPK-II : an increase in the concentration of the enzyme in S3 and a corresponding decrease in P2M with no overall change in the total amount of enzyme and little apparent change in the concentration of other proteins. In both fractions, there was a parallel change in the Ca2+/calmodulin-stimulated phosphorylation of endogenous protein substrates but no change in the basal or cyclic AMP-stimulated protein phosphorylation. Supplementing the PTU/MMI-treated diet with thyroxine (0.5 ppm) prevented all of the observed changes.

Successful treatment with carbimazole of a hyperthyroid pregnancy with hepatic impairment after propylthiouracil administration: a case report.

Abstract: We report the case of a 27-year-old woman with hyperthyroidism during pregnancy. Antithyroid treatment with propylthiouracil (PTU) resulted in elevated hepatic enzymes and after the 12th week of pregnancy treatment was changed to carbimazole (CBZ). The remaining pregnancy, delivery and follow-up period were uneventful for the mother and her offspring. Antithyroid treatment during pregnancy should allow the use not only of PTU but also of CBZ and methimazole.

Anatomical changes in CA3 hippocampal region by hypothyroidism in rats.

Abstract: Thyroid hormones exert a crucial role in trophic events of the CNS during development, adulthood and aging. In fact, the lack of thyroid hormones leads to a dramatic impairment of mental performance [1]. The hippocampus, which has been related with many cognitive functions and with epileptic processes [2], is particularly affected by hypothyroidism. It has been observed that a decrease in serum thyroid hormones induces morphological changes in CA3 hippocampal region [3]. Previous studies carried out in our laboratory have shown that a decrease in serum thyroid hormones in adult rats increases susceptibility to lidocaine and pentylenetetrazole-kindling seizures [4,5]. The mechanisms of this increased susceptibility are unknown but could be related to the morphological changes observed in hypothyroid rats [3]. Considering that in our previous studies the hypothyroid state was induced by a chronic treatment with methimazole (MMI), we carried out this study in rats using MMI and propylthiouracil (PTU) as antithyroid drugs, with the goal to determine if the morphological changes observed previously in CA3 pyramidal cells are caused by the antithyroid drugs directly or via the lack of thyroid hormones.

Neonatal thyrotoxicosis and maternal infertility in thyroid hormone resistance due to a mutation in the TRβ gene (M313T)

Abstract: Summary We report two unusual cases of resistance to thyroid hormone (RTH) in one family. The first case, a male infant, had clinical features of thyrotoxicosis in the neonatal period. In the fourth week of life weight gain was poor despite a daily intake of standard infant formula almost double the infant's estimated requirements. At this time serum free T4 (fT4) was 60·7 pmol/l (Normal range [NR] 11–25 pmol/l) and TSH was inappropriately normal at 1·8 mU/l (NR 0·3–4·0 mU/l). The infant responded clinically and biochemically to propylthiouracil (PTU) at a dose of 10 mg/kg/day. Following 27 days of treatment serum fT4 was 22·6 pmol/l and TSH had risen to 24·9 mU/l. As the infant was thriving treatment was discontinued. The infant, now aged 6 months old, remains clinically euthyroid and developmentally normal off treatment. The infant's mother, from whom he had inherited a mutation of the thyroid receptor β (TRβ) gene (M313T), presented earlier with secondary infertility and clinical features of thyrotoxicosis. Treatment with PTU restored her fertility and she spontaneously conceived. In the subsequent pregnancy, clinical and biochemical features of RTH improved, and she gave birth to a small but healthy female infant. In the next pregnancy, resulting in the birth of the affected male infant, clinical and biochemical features of RTH worsened, and high doses of PTU were required to maintain a clinically euthyroid state. To our knowledge, these are the first case reports of RTH associated with added features of a hypermetabolic state in infancy and secondary infertility.

Effect of iodide on Fas, Fas-ligand and Bcl-w mRNA expression in thyroid of NOD mice pretreated with methimazole

Abstract: Nonobese diabetic (NOD) mice and a derived strain, NOD.H.2h4, have been used as a model for experimental spontaneous thyroiditis and thyroiditis induced by iodide excess after a goiter-inducing period. Some authors have proposed that iodide, given after methimazole or propylthiouracil, is capable of inducing apoptosis in thyroid cells and that anti-thyroid drugs can modulate the expression of apoptosis components such as Fas and its ligand (Fas-L). Here we evaluated the effect of potassium iodide (20 µg/animal for 4 days, ip) given to NOD mice at the 10th week of life after exposure to methimazole (1 mg/ml) in drinking water from the 4th to the 10th week of life. Fas, Fas-L and Bcl-w expression were analyzed semiquantitatively by RT-PCR immediately after potassium iodide administration (group MI44D) or at week 32 (MI32S). Control groups were added at 10 (C10) and 32 weeks (C32), as well as a group that received only methimazole (CM10). An increase in the expression of Fas-L and Bcl-w (P<0.01, ANOVA) was observed in animals of group MI44D, while Fas was expressed at higher levels (P = 0.02) in group C32 (72.89 ± 47.09 arbitrary units) when compared to group C10 (10.8 ± 8.55 arbitrary units). Thus, the analysis of Fas-L and Bcl-w expression in the MI44D group and Fas in group C32 allowed us to detect two different patterns of expression of these apoptosis components in thyroid tissue of NOD mice.

Influência do hipogonadismo na histomorfometria e função tireoidiana de ratas hipotireóideas

Abstract: The morphology and function of the thyroids of female adult Wistar rats were investigated. The animals were either castrated or intact and kept in a hypothyroid condition by a treatment with propylthiouracil for 120 days. Castrated and intact euthyroid rats were used as controls. The thyroids were collected at the end of the experiment, weighted, histologically processed, and morphometrically evaluated. Proportions of each glandular component, namely, follicular epithelium, colloid, and stroma, were determined. Serum concentrations of total T3, free T4, and TSH were assessed at the end of the experimental period. The weight and the morphometric parameters were not influenced by castration, whereas an increase in the epithelial component associated with a decreased amount of colloid were observed only in hypothyroid animals. Under an euthyroid state, the deficiency of sexual hormones induced an increase in the levels of free T4 and total T3. In hypothyroid animals, withdrawal of sexual hormones caused an exacerbation of the decrease in total T3, but not in free T4. TSH levels were not affected by the thyroid or the functional condition of gonads. In conclusion, hypogonadism did not influence the glandular hyperplasia and decrease in plasmatic levels of free thyroxin induced by propylthiouracil, but markedly changed the profile of total T3 according to the functional condition of the thyroid, in the absence of changes in the plasmatic levels of TSH.

The antipsoriatic effect of thiamazole is not accompanied either by significant changes in blood lymphocyte subsets nor by serum concentration of TNF-alpha

Abstract: It has been reported that the antithyroid thiourethylenes, propylthiouracil and methimazole can bring about significant clinical improvement in patients with psoriasis vulgaris. In this paper, we reconfirmed the clinical usefulness of the antithyroid drug thiamazole, which is similar to methimazole, in Japanese patients with psoriasis vulgaris. We further asked whether the clinical improvement was linked to the changes in some immunological parameters or not. To answer this question, we analyzed peripheral blood lymphocyte subsets and measured serum concentrations of TNF-alpha and IL-1beta in 13 patients with psoriasis vulgaris before and during thiamazole administration. The mean percentage of CD4+ HLA-DR+ lymphocytes in the patients was constantly elevated before and 12 weeks after the administration. The patients treated with thiamazole showed a significant increase in the ratio of CD4+/CD8+ at the 4th week, though it declined at the 8th and 12th week. Other lymphocyte subsets showed no significant change during the treatment. The concentrations of serum TNF-alpha exhibited no significant change during thiamazole administration. Serum concentration of IL-1beta was under the detection level. These results indicate that thiamazole may improve the psoriatic lesion via other immune mechanisms, or the effects can not be reflected by the peripheral lymphocyte subsets and cytokine which we investigated.

A successful pregnancy and delivery case of Graves' disease with myeloperoxidase antineutrophil cytoplasmic antibody induced by propylthiouracil.

Abstract: A 30-year-old female patient, diagnosed as having Graves’ disease in 1996, was treated with propylthiouracil (PTU) for 4 years. She developed a low-grade fever from December 1999. As myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) vasculitis is one of the adverse effects of PTU, we examined serum MPO-ANCA level and found it was positive, but cytoplasmic-ANCA (c-ANCA) was negative. There were no symptoms that indicated other diseases associated with MPO-ANCA. She was confirmed to be at 6 weeks gestation, and thyroid hormone levels were elevated at that time. We discontinued PTU and gave methyl-mercaptoimidazole (MMI), and the titer of MPO-ANCA fell along with fever. Therefore we estimated the case as probable MPO-ANCA positive vasculitis induced by PTU. MMI was also suspended because of the development of hepatic dysfunction. After thyroid function was normalized by administration of potassium iodide, she underwent subtotal thyroidectomy, and delivered a 2350 g infant at 38 weeks’ gestation, which was less than the normal birth weight of 2400 g. MPO-ANCA is considered to be one reason of low birth weight infant including hyperthyroidism. It is necessary to consider the appearance of the possibility of MPO-ANCA positive vasculitis in patients who are treated with PTU.

Aplasia Cutis Congenita and Dysmorphic Syndrome After Antithyroid Therapy During Pregnancy

Abstract: Aplasia cutis congenita (ACC) is alleged to be a side effect of antithyroid therapy during pregnancy. This occurrence is uncommon. Only 24 cases have been reported in the literature. In France, there has been no report by the National Center of Pharmacovigilance since 1985. We report a 39-year-old woman with no significant past history in whom Graves disease developed without eye symptoms. She was using methimazole 60 mg daily for 3 months, followed-up by propylthiouracil until delivery. At birth, the newborn had a scalp defect on the vertex, measuring 7- × 2-cm, transient hypothyroidism, and a dysmorphic syndrome (flat face, low-set ears, upper lip retraction, xiphoid funnel, finger-like claws, and low-set fifth finger). At age 1 year, the aplasia cutis was treated surgically. Aplasia cutis is a rare disorder, sometimes associated with other malformations. The mothers with hyperthyroidism who delivered children with reported cases of ACC have used either carbimazole or its active metabolite, methimazole, during early pregnancy. The relationship between methimazole or carbimazole therapy during pregnancy and ACC in the newborn remains to be proven. Nevertheless, to the authors’ knowledge, no case has occurred in which the mother has used only propylthiouracil. Therefore, consideration should be given to the exclusive use of propylthiouracil in pregnancy.

Fatal thyroid crisis years after two thyroidectomies for graves' disease: is thyroid tissue autotransplantation for postthyroidectomy hypothyroidism worthwhile?

Abstract: We read with great interest about the trial of autotransplantation of cryopreserved thyroid tissue for postoperative hypothyroidism in patients with Graves’ disease by Dr Shimizu and colleagues that was published in the January 2002 issue of this journal. The idea of eliminating the need for lifelong L-thyroxine replacement because of thyroprivic hypothyroidism undoubtedly appeals to the patients. But what concerns us is that three out of the four subjects who consented to the procedure did so with a view to relieve them from frequent followup visits. Although the authors maintained that the appropriate amount of thyroid tissue could be easily removed from the forearm under local anesthesia should recurrent hyperthyroidism occur, it should be appreciated that an inherent risk exists in selecting such subjects for this procedure. Because these patients opted for autotransplantation with a view to decrease the need for frequent longterm followups, they are also exposed to the risk of severe or even potentially fatal thyroid crisis should there be undue delay in the detection and treatment of a relapse. As to the point that no cases of recurrent hyperthyroidism have been seen as a result of autotransplantation of thyroid tissue, such a conclusion is premature and would require careful evaluation of a large number of subjects over an extended period of followup to be certain. The incidence of relapse of thyrotoxicosis in those who had subtotal thyroidectomy can approach 18%, and the mean duration to relapse postthyroidectomy ranges from less than a year to 30 years or more. For those who relapsed after subtotal thyroidectomy, we would favor iodine therapy with the aim of achieving total thyroid ablation. This is because Graves’ disease, unlike other forms of hyperthyroidism, carries a persistent risk of relapse whenever remnant thyroid tissue is left behind. To underscore our point, we report a patient presenting with severe thyroid storm despite two previous thyroidectomies for persistent thyrotoxic Graves’ disease. The patient was a 53-year-old Chinese woman who first underwent subtotal thyroidectomy in 1980 after 2 years of failed thionamide therapy. Because of a relapse 3 years later, a near-total thyroidectomy was done in 1983. She remained biochemically and clinically euthyroid for nearly 18 years after the two operations. On April 19, 2001, she developed pneumonia and was admitted to the hospital. Clinically, she was pyrexial, diaphoretic, and stuporous. A prominent lid-lag with lid retraction was present, accompanied by fine tremors of her upper extremities. A thyroidectomy scar was visible, with no palpable thyroid tissue. She was in rapid atrial fibrillation and congestive cardiac failure. She was evidently suffering from thyroid storm, and propylthiouracil and sodium iodide were initiated after blood samples were collected. Propranolol was administered cautiously with digoxin and diuretics to control her heart failure. Initial blood investigations revealed free T4 61pmol/L (normal range 10–20), free T3 15.7pmol/L (normal range 5.8– 8.7), thyroid stimulating hormone (TSH) 0.01mIU/L (normal range 0.40–3.98), and TSH receptor autoantibody 17.8U/L (normal range 3.4). Over the next 5 days, she remained tachypneic and hypotensive. She died from multisystem failure 5 days later. This case serves as a grave reminder that surgical resection of the thyroid in Graves’ disease, no matter how radical it is, does not always render the patient permanently hypothyroid or confer absolute immunity to future recurrence of the illness. So we advocate iodine therapy to achieve total thyroid remnant ablation in patients with persistently active thyroid autoimmunity presenting with relapse postthyroidectomy. Relapse of thyrotoxicosis after near-total thyroidectomy is estimated at about 3%. Thyroid crisis complicating the longterm course of near-total thyroidectomy is believed to be an exceedingly rare occurrence. Our patient led us to consider what critical amount of thyroid tissue remnant could confer a significant risk of relapse of thyrotoxicosis. Although past researchers had established that the probability of relapses becomes in-

[A 35-year-old man with gynaecomastia as the first symptom of hyperthyroidism].

Abstract: A 35-year-old man suffered painful bilateral gynaecomastia for 2 months due to serious Graves' hyperthyroidism. During treatment with propylthiouracil and levothyroxine, the plasma concentrations of thyroid hormone, sex hormones and sex hormone-binding globulin normalised and the gynaecomastia disappeared. Gynaecomastia occurs in 30 to 40% of men diagnosed with Graves' hyperthyroidism. However, gynaecomastia as a presenting symptom of this autoimmune disease is uncommon.