propylthiouracil and Hypertrophy

A 71-year-old man with hyperthyroidism complained of headache lasting two months. He had been using propylthiouracil (PTU) for 14 years. Treatment intensification did not improve the symptoms. Blood tests detected a positive myeloperoxidase-anti-neutrophil cytoplasmic antibody (MPO-ANCA). Diffuse dural thickening was identified by magnetic resonance imaging. The patient was diagnosed with hypertrophic pachymeningitis (HP) due to ANCA-associated vasculitis (AAV). He received methylprednisolone pulse therapy followed by prednisolone and methotrexate, which improved his headache. PTU-induced AAV-related HP is a rare and indiscernible disease. Therefore, the possibility of the disease should be proactively considered when a PTU user experiences refractory headaches.

Topics: Aged; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Antineutrophil Cytoplasmic; Antithyroid Agents; Headache; Humans; Hypertrophy; Male; Meningitis; Peroxidase; Propylthiouracil

Although measurements of blood hormone levels in rodent toxicological studies can provide important information on the mechanisms of toxicity and extrapolation to humans, there are several difficulties such as large individual differences and limited sample volume. To develop a more simplified method that does not depend solely on blood samples, we examined the possible application of immunohistochemistry for detecting endocrine disruptors in short-term studies. Aminotriazole (AMT), propylthiouracil (PTU), phenobarbital, aminoglutethimide (AGT), estradiol, and vitamin D3 were administered orally to 6-week-old male and female SD rats (five/group) for 28 days. Measurements of serum hormone levels revealed decreases in triiodothyronine (T3) and thyroxine (T4) in the AMT and PTU groups, an increase in thyroid stimulating hormone (TSH) in the AMT, PTU, and AGT groups, and an increase in adrenocorticotrophic hormone in the AGT group. Increased thyroid, pituitary, and adrenal gland weights; histopathological lesions, including follicular hypertrophy/hyperplasia, hypertrophy/vacuolation of anterior pituitary cells, and increased adrenocortical vacuolation were observed in association with the hormone level changes. Immunohistochemical analysis revealed a decreased T4 level in the thyroid gland of the AMT and PTU groups and an increased area of TSH positive immunostaining in the pituitary gland of the AMT, PTU, and AGT groups, consistent with the changes in serum T4 and TSH levels, respectively. These results suggest that histopathological analysis and immunohistochemistry for T4 and TSH might be useful and sensitive methods of detecting thyroid dysfunction, and that combining organ weight measurements is a reliable parameter of detecting endocrine disruptors.

Topics: Animals; Endocrine Disruptors; Female; Humans; Hypertrophy; Male; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyrotropin; Thyroxine; Triiodothyronine

The perchlorate discharge assay (PDA) is potentially of high diagnostic value to distinguish between direct and indirect thyroid toxicity mechanisms, provided that standard treatment times are established and positive controls yield reproducible results. Therefore the PDA was evaluated after 2 and/or 4 weeks of treatment with positive control compounds in rats. Phenobarbital, Aroclor 1254 and beta-naphthoflavone (indirect toxic mechanism) enhanced thyroidal radioiodide accumulation, and the administration of potassium perchlorate had no effect on thyroid: blood (125)I ratio. Phenobarbital caused follicular cell hypertrophy and hyperplasia in the thyroid and centrilobular hypertrophy in the liver, without effects on serum triiodotyronine (T(3)), thyroxine (T(4)) levels. Thyroid-stimulating hormone (TSH) levels were moderately increased. Propylthiouracil (direct toxic mechanism) caused severe thyroid follicular cell hypertrophy and hyperplasia, reduced serum T(3) and T(4) levels and increased serum TSH levels, and reduced thyroidal radioiodide accumulation; perchlorate administration significantly reduced thyroid: blood (125)I ratio, demonstrating an iodide organification block. Potassium iodide (direct toxic mechanism) virtually blocked thyroidal radioiodide accumulation, without significant effects on serum T(3), T(4), and TSH levels and a microscopic correlate for higher thyroid weights. Thus, positive controls yielded reproducible results and we conclude that both the 2- and 4-week PDA is suitable to distinguish between direct and indirect thyroid toxicity mechanisms.

Topics: Animals; beta-Naphthoflavone; Chlorodiphenyl (54% Chlorine); Hyperplasia; Hypertrophy; Iodine Radioisotopes; Male; Perchlorates; Phenobarbital; Potassium Compounds; Potassium Iodide; Propylthiouracil; Rats; Rats, Wistar; Reproducibility of Results; Sensitivity and Specificity; Thyroid Function Tests; Thyroid Gland; Thyrotropin; Thyroxine; Toxicity Tests; Triiodothyronine

The aim of this study was to evaluate in vivo the antiproliferative effect of an inhibitor of isoprenoids metabolism, lovastatin, in an experimental model of propylthiouracil-induced goiter. In thyroid cells, thyrotropin (TSH)-induced proliferation requires active isoprenoid synthesis, and the HMG-CoA reductase inhibitors have antiproliferative effects in vitro. Propylthiouracil treatment (PTU) of rats led to thyroid hypertrophy and hyperplasia by TSH-induced activation of the mitogen-activated protein kinase (MAPK) pathway. Immunohistochemistry showed an increased number of proliferating cell nuclear antigen (PCNA)-positive cells in the thyroid gland of PTU-treated rats. Moreover, the phosphorylation of ERK1 and ERK2 was increased in the extract from goiter tissue as compared with the thyroid tissue of untreated rats. To determine whether the inhibition of selected pro-survival pathways (i.e., p21ras-MAPK) was sufficient to affect goitrogenesis, thyroids from 12 PTU-treated rats were injected in vivo with an adenovirus transducing a dominant-negative ras gene (Rad-L61.S186) and another set of 12 rats were injected with a pharmacological inhibitor of MAPK (PD98059). Both Rad-L61.S186 and PD98059 were able to inhibit the PTU-induced goiter. It is interesting to note that lovastatin, when administered in drinking water, significantly prevented the thyroid gland enlargement. Therefore, lovastatin-treated thyroid glands were significantly smaller than those treated with PTU alone. In addition, the lovastatin-treated glands also showed a decreased expression of phosphorylated ERK1/2 and a number of PCNA-positive cells. Our data suggest that lovastatin is an efficient inhibitor of goitrogenesis and provide a rationale for innovative therapeutic strategies employing statins in the treatment of nodular goiter in humans.

Topics: Animals; Disease Models, Animal; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Gene Transfer Techniques; Goiter; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperplasia; Hypertrophy; Lovastatin; Male; MAP Kinase Signaling System; Phosphorylation; Proliferating Cell Nuclear Antigen; Propylthiouracil; Protein Kinase Inhibitors; Protein Prenylation; ras Proteins; Rats; Rats, Wistar; Terpenes; Thyroid Gland; Thyrotropin

We have studied the effects of propythiouracil (PTU) or perchlorate (CIO(4)(-)), given to the mothers' drink from the 15(th) day of pregnancy until the day of sacrifice, on thyroid function of suckling mice. Antihyroid drugs (PTU or CIO(4)(-)) provoked growth perturbations of young mice during studied ages from 6 to 18 days. A decrease of body weight was respectively as follows: 14 and 22% in 6 day-old mice; 16 and 23% in 10 day-old mice; 18 and 18% in 14 day-old mice; 19 and 11% in 18 day-old mice. We have noticed an hypertrophy of thyroid glands of pups and their mothers caused by an increase of pituitary TSH. Thyroid follicles presented the aspect of hypothyroid animals with an increase of follicular number and vascularisation. Structural modifications confirmed biochemical results. In fact thyroid iodine contents decreased strongly in young as follow: 40 and 43% in 6 day-old mice; 51 and 50% in 10 day-old mice; 66 and 84% in 14 day-old mice; 54 and 89% at 18 day-old mice and in their mothers (50, 37%; 59, 54%; 75, 65% and 85, 72%) respectively after PTU or CIO(4)(-) treatment. A decrease of iodine thyroid gland was accompanied by an important fall of free thyroid hormones levels (FT3 and FT4) in young and adult mice. A decrease of thyroid hormonemia could explain the pups' growth perturbations.

Topics: Aging; Animals; Antithyroid Agents; Female; Hypertrophy; Iodine; Lactation; Maternal-Fetal Exchange; Mice; Perchlorates; Pituitary Gland; Pregnancy; Propylthiouracil; Sodium Compounds; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

We studied the effects of semotiadil fumarate (SF), a new calcium antagonist with a unique benzothiazine structure, on the thyroid gland and liver in rats and compared them with those of another calcium antagonist, nicardipine (NCD), a well-known thyroidal hypertrophic agent and microsomal enzyme inducer, phenobarbital (PB), and goitrogen propylthiouracil (PTU). In oral 2-week treatment, SF caused increases in hepatic microsomal protein levels, uridine diphosphate glucuronosyltransferase (UDPGT) activity and an increase in serum thyroid stimulating hormone (TSH) level together with decreases in serum thyroid hormone levels. These results suggest that SF accelerates peripheral disposition of thyroid hormones and subsequently stimulates secretion of TSH from the pituitary gland as a compensatory response. PB and NCD had similar effects on the thyroid gland and the liver. PTU showed obvious thyroid hyperplasia and an increase in relative liver weight. Drastic increase in TSH level was observed in the PTU-treated group together with significant decreases in serum thyroid hormone levels and an increase in hepatic UDPGT activity. Histopathologically, PTU depleted the colloids in follicles, suggesting the inhibition of thyroid hormone synthesis. SF, PB and NCD showed thyroidal hyperplasia, but the extent of the change was far more moderate than that induced by PTU. These results indicate that the effect of SF is similar to those of PB and thyroid hypertrophy seen in the oral 2-week treatment with SF, and may be caused by indirectly elevated TSH levels which resulted from the induction of hepatic UDPGT activity.

Topics: Animals; Calcium Channel Blockers; Female; Glucuronosyltransferase; Hyperplasia; Hypertrophy; Liver; Microsomes, Liver; Nicardipine; Phenobarbital; Propylthiouracil; Rats; Rats, Wistar; Thiazoles; Thyroid Diseases; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

Our previous studies have shown that transient neonatal hypothyroidism, induced by treatment with the reversible goitrogen 6-propyl-2-thiouracil (PTU), increases testicular size and daily sperm production in the adult rat by up to 82% and 136%, respectively. The objective of the present study was to examine morphological and functional changes in adult seminiferous tubules associated with PTU-induced increases in testicular size and sperm production. Sprague-Dawley rats were treated with PTU from birth to day 25 or left untreated; for morphometry, all testes were fixed by vascular perfusion at 90 days of age. Although testicular weight was increased 62% in treated rats, gross pathological changes were not evident in these organs, and spermatogenesis appeared morphologically normal. The percent area of testis occupied by seminiferous tubules was equal in control and treated testes, but mean seminiferous tubule diameter and length were increased in the PTU-treated testis. The adult number of Sertoli cells in treated testes was increased by 157%, and the numbers of leptotene spermatocytes and round spermatids were increased 84% and 93%, respectively. These results demonstrate that increases in Sertoli cell numbers result in increased sperm production and support the idea that Sertoli cells are the major regulators of the magnitude of sperm production. Although the round spermatid to Sertoli cell ratio was reduced by nearly 30%, the number of round spermatids per g testis was increased by 14%. This increased efficiency of sperm production was accomplished by an increased density of Sertoli cells along the basement membrane and an increased height of the seminiferous epithelium. Despite the large increase in Sertoli cell numbers in treated rats, Northern blot analysis using Sertoli cell-specific cDNA probes for transferrin and androgen-binding protein indicated that relative steady state levels of mRNAs per Sertoli cell for these two secretory proteins were similar in control and treated rats at 90 days of age.

Topics: Animals; Animals, Newborn; Blotting, Southern; Cell Count; Germ Cells; Hypertrophy; Hypothyroidism; Male; Propylthiouracil; Rats; Sertoli Cells; Testis

The effects of various durations of postnatal hypothyroidism followed by recovery were studied on testicular growth in Long-Evans and Sprague-Dawley rats from birth to 7 months. Hypothyroidism was induced by adding propylthiouracil (PTU) in drinking water (0.1%, w/v). Recovery was induced by withdrawal of PTU. Testicular growth was reduced in rat pups by 20, 65 and 90% at days 10, 25 and 50. Upon withdrawal of PTU at weaning (25 days), testicular growth resumed and became compensatory; catch-up growth occurred by day 65. Paradoxically, testicular growth progressively increased, surpassing the control weights by 40, 50 and 100% at days 75, 90 and 210. Maximal testicular growth rate in the recovery group was 35% higher, occurred 2 weeks later and lasted 2 weeks longer than controls. Testes of rats subjected to prolonged postnatal hypothyroidism (60 or 120 days) also showed recovery and hypertrophy, amounting to nearly twice the normal maximal growth levels, after at least 6 months of recovery. Body weights of recovering rats remained always significantly below those of controls. When the suckling pups were exposed to short, week-long regimes of PTU treatment, only rats treated during the early postnatal weeks (days 1-8 or 9-16) had enlarged testes; PTU treatment during the late suckling period (days 17-24) or later had no effects. Total duration of hypothyroidism in the suckling period was positively correlated with testicular enlargement. The results indicate that hypothyroidism early in life is stimulatory to testicular growth, resulting in a paradoxical twofold increase in final testicular size which occurs even if hypothyroidism is prolonged. These effects occur similarly in different strains of rat with differing sized testes. It is suggested that there is a sensitive period for this effect, i.e. during the first 2 weeks after birth. The marked plasticity of testicular growth as shown by its recovery and hypertrophy, even after long periods of hypothyroid retardation, is unique in the body and may be a useful model for studying hormonal factors regulating testicular growth and for animal breeding and research into infertility.

Topics: Animals; Animals, Suckling; Hypertrophy; Hypothyroidism; Male; Organ Size; Propylthiouracil; Rats; Rats, Sprague-Dawley; Testis; Time Factors

Hypothyroid-induced atrophy of cardiac myocytes was examined in adult female rats in an effort to correlate hemodynamic and cellular changes associated with this disorder. Additional rats were studied 6 weeks after discontinuing antithyroid treatment to determine if structural and functional changes were completely reversible. To induce hypothyroidism, rats were injected daily with propylthiouracil (PTU) for 4 weeks. Control animals were injected similarly with Tris buffer. At the end of the treatment period, hemodynamic measurements were made prior to obtaining isolated myocytes. Cell volume, length, and cross-sectional area were obtained from the septum, and left and right ventricles of treated and untreated rats. After four weeks treatment with PTU, body weight was unchanged but heart weight was significantly reduced by 24%. Characteristic hemodynamic changes associated with hypothyroidism in the rat were noted (eg. reduced heart rate, cardiac output, dP/dtmax, and ventricular pressure). Cell volume was significantly smaller in hypothyroid rats primarily due to a reduction in myocyte cross-sectional area. The hemodynamic and cellular response to hypothyroidism was similar in the right and left ventricle. Six weeks after discontinuing PTU treatment, cellular and hemodynamics changes had returned to normal. It was concluded that hypothyroidism caused a true cardiac atrophy which was reversible. Reduced myocyte cross-sectional area was responsible for most of the myocyte atrophy.

Topics: Animals; Female; Hemodynamics; Hypertrophy; Hypothyroidism; Myocardium; Propylthiouracil; Rats; Rats, Inbred Strains

Goitre growth was investigated in rats receiving a low iodine diet (less than 0.1 microgram iodine/g) and either 1 g/l KClO4 or 1 g/l propylthiouracil (PTU), or a combination of KClO4 or PTU with 50.82 nmol/1 T3 in tap water for 3 weeks. To investigate goitre involution, rats with iodine-deficient goitres were treated for 3 weeks either with T3 (0.5 microgram T3/day = 0.768 nmol/day), iodide (0.5 or 2.7 micrograms KI/day) or a combination of T3 with both iodide doses. Histology together with total DNA distinguished between hypertrophy and hyperplasia of the gland. During goitre growth there was highly significant correlation between goitre weight and TSH serum level (r = 0.93, P less than 0.001). Thyroid total DNA, however, was only weakly correlated to TSH but was inversely related to the degree of iodine deficiency. During goitre regression, TSH levels were normalized, histological signs of hypertrophy had disappeared, and thyroid weight was nearly normalized in all therapy groups. Total DNA, however, was normalized only with 2.7 micrograms KI/day (95 +/- 18 micrograms DNA/gland), and still elevated in all other groups. The highest DNA levels were found under T3 therapy (143 +/- 21 micrograms DNA/gland) and under 0.5 microgram KI/day (161 +/- 19 micrograms DNA/gland). Reduction of total DNA was independent of TSH, but followed replenishment of the iodine content of the glands. We conclude that TSH mainly induces hypertrophy, whereas thyroid hyperplasia is mainly regulated by the intracellular iodine content.

Topics: Animals; DNA; Female; Goiter; Hyperplasia; Hypertrophy; Iodine; Male; Organ Size; Potassium Chloride; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Gland; Thyrotropin; Triiodothyronine

After 2 weeks of goitrogen treatment [propylthiouracil (PTU), 0.02% in drinking water], the thyroids of rats increased to 280% of control wet weight, 270% of dry weight, and 250% of control DNA content. Two phases of growth were apparent, an initial hypertrophy phase lasting 3 days (increase in cell size and gland weight with no detectable increase in DNA) and a hyperplastic phase (increase in DNA with histological evidence of cell proliferation) starting at 3-4 days and continuing through 14 days. The cyclic AMP-dependent protein kinase activity ratio (-cyclic AMP/+cyclic AMP) showed a biphasic pattern during the 2-week thyroid growth period, with maxima at day 1 (132% of control) and day 6 (148% of control). Ornithine decarboxylase (EC 4.1.1.17), the initial enzyme in polyamine biosynthesis, showed a similar biphasic pattern with a 6- to 7-fold elevation in activity at 2-3 days and a 4-fold elevation at 6 days. S-Adenosyl-L-methionine decarboxylase (EC 4.1.1.50), the enzyme which catalyzes spermidine synthesis, was elevated 4-fold at 9 days of treatment. The thyroid total supernatant protein kinase activity (+cyclic AMP) increased to 160% of control by 4 days, returning to control by 14 days of PTU treatment. The thyroid had 10% Type I activity and 90% Type II cyclic AMP-dependent protein kinase activity. The specific activity of both Types I and II remained unchanged for the first 2 days of PTU treatment. Both types increased to 150% of control by 4 days. Type I remained elevated throughout the remainder of the 14 days, in contrast to Type II, which decreased conspicuously to control levels by 6 days. A single injection of thyroid-stimulating hormone (TSH, 1.0 unit/100 g of body weight, i.p.) resulted in a 20-fold increase in thyroid ornithine decarboxylase activity by 4 hr. The same dose of TSH produced only a 3-fold induction of ODC in rats hypophysectomized 2 weeks previously. The thyroid specific activity of Types I and II protein kinase was only 55% and 57% of control, respectively, in these unresponsive rats. Thyroids from rats chronically stimulated for 14 days showed an increase in ornithine decarboxylase following TSH administration similar to that of control rats. Changes in the activation as well as specific activity of Types I and II protein kinase during hypertrophy and hyperplasia underlie the complexity of a cyclic AMP-mediated response.

Topics: Adenosylmethionine Decarboxylase; Animals; Carboxy-Lyases; Cyclic AMP; Hyperplasia; Hyperthyroidism; Hypertrophy; Kinetics; Male; Ornithine Decarboxylase; Polyamines; Propylthiouracil; Protein Kinases; Rats; Rats, Inbred Strains; Thyroid Gland

Topics: Animals; Chickens; DNA; Glucosephosphate Dehydrogenase; Hypertrophy; Muscular Dystrophy, Animal; Pectoralis Muscles; Phosphogluconate Dehydrogenase; Propylthiouracil; Thyroid Gland; Thyroxine; Triiodothyronine

Topics: Animals; Chickens; Chromatography, DEAE-Cellulose; Cyclic AMP; Female; Hypertrophy; Isoenzymes; Organ Size; Pituitary Gland, Anterior; Propylthiouracil; Protein Kinases; Thyroid Gland

The effect was studied of biochemical and morphological changes induced by antithyroid substances (PTU, C10(-4)) on proton spin-relaxation properties of rat thyroid gland. It was found that thyroid stimulated by PTU (0.05%) or C10(-4) (1.0%) exhibit marked morphological changes (hyperplasia and epithelial hypertrophy) with alteration of the soluble iodoprotein pattern (content and composition.). Both relaxation times spin-lattice (T1) and spin-spin (T2) were increasing with the lenght of treatment with antithyroid drugs. Reversibility of the process was noted in accordance with biochemical and morphological data. The relaxation rate (formula: see text) for thyroid tissue water was in positive correlation with the suluble protein concentration and particularly with the TG content in the gland. There was no difference in relaxation times between normal thyroid and gland of rats treated chronically with excess iodide. The observed difference in T1 between normal glands and glands of PTU,-C10(-4)--treated rats was comparable with that found in cases of human thyroid cancer. This finding is of importance when the diagnostic potential of NMR in the detection of malignancy is considered. In conclusion, a strong correlation was found between microstructural and biochemical changes of the thyroid gland and proton magnetic relaxation of tissue water. The striking difference between the proton spin-relaxation times in normal and in goiter thyroid glands of rats suggests that pulsed NMR spectroscopy could be a method for evaluation of some disturbances in thyroid gland.

Topics: Animals; Body Water; Hyperplasia; Hypertrophy; Iodoproteins; Magnetic Resonance Spectroscopy; Male; Perchlorates; Propylthiouracil; Protons; Rats; Thyroid Diseases; Thyroid Gland

Topics: Animals; Castration; Ducks; Female; Hybridization, Genetic; Hyperplasia; Hypertrophy; Male; Pituitary Gland; Propylthiouracil; Thyroidectomy; Thyrotropin

Topics: Animals; Castration; Female; Hypertrophy; Hypothyroidism; Organ Size; Ovary; Pituitary Gland; Propylthiouracil; Rats; Thyroidectomy

Topics: Animals; Endoplasmic Reticulum; Female; Hypertrophy; Hypothyroidism; Male; Microscopy, Electron; Pituitary Gland; Prolactin; Propylthiouracil; Rabbits; Thyroidectomy

Topics: Animals; Antithyroid Agents; Body Weight; Bursa of Fabricius; Caseins; Chickens; Comb and Wattles; Fasting; Hepatomegaly; Hypertrophy; Hypothyroidism; Liver; Liver Glycogen; Male; Organ Size; Propylthiouracil; Testis; Thiouracil; Thyroid Gland

Topics: Adrenal Glands; Animals; Atrophy; Female; Fetal Diseases; Goiter; Guinea Pigs; Hyperplasia; Hypertrophy; Pituitary Gland; Pregnancy; Pregnancy, Animal; Propylthiouracil; Thyroid Gland

Topics: Adrenal Glands; Adrenalectomy; Adrenocorticotropic Hormone; Animals; Estradiol; Female; Hypertrophy; Hypothalamo-Hypophyseal System; Infertility, Female; Organ Size; Propylthiouracil; Rats; Testosterone; Thyroid Gland; Thyrotropin

Topics: Hypertrophy; Kidney; Nephrectomy; Propylthiouracil; Thiouracil

Topics: Animals; Cell Communication; Hypertrophy; Hypothalamus; Propylthiouracil; Rats; Thiouracil; Thyroid Gland; Thyrotropin; Thyroxine