propylthiouracil and Hyperplasia

To explore the mechanism and the compensation proceeding of thyroid hyperplasia caused by PTU.. PTU was administered to rats by gavage at a dose of 5.0 mg/kg B. W for 3, 6, 9, 12, 15, 18, 21 days respectively. All animals were sacrificed after the last dosage, and the expression of TPO and Tg in thyroid was detected by RT-PCR. The serum thyroid hormones were measured by chemoluminescence.. Compared with the control group, the TPO mRNA levels of PTU groups were increased, while the Tg mRNA levels were decreased significantly. Serum TT3, TT4 in rats treated with PTU demonstrated a descending trend, while serum TSH showed an ascending trend, and the significant differences were observed after 6 days treating with PTU.. The interference of PTU on thyroid may relate to inhibiton of Tg gene transcription. The enhancement of TPO gene transcription can't compensate the thyroid function sufficiently.

Topics: Animals; Endocrine Disruptors; Hyperplasia; Iodide Peroxidase; Male; Propylthiouracil; Random Allocation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Thyroglobulin; Thyroid Gland

Establish an effective method for in vivo short-time standardized discriminating system of thyroid hormone disruptors.. 4 experimental groups treated with PTU lavage for 3, 6, 9, 12 days respectively and one dissolvent group for control. 10 rats in each group were sacrificed in due time with the serum being extracted and detected for T3, T4 and TSH by chemoluminescence. Histopathological changes were visualized by HE staining and changes in colloid were visualized by PAS staining. PCNA was detected by IHC and western-blotting.. Comparing with control group, 3-day treated started to show a decrease in serum concentration of TT3 (P < 0.05), 6-day, 9-day and 12-day treated presented significant decreases in both concentration of TT3 and TT4, with a significant increase in TSH concentration (P < 0.05). Viscera coefficients of thyroid gland were significantly greater than the controls in 6-day, 9-day and 12-day treated groups (P < 0.05). Histopathological observation found thyroid follicle epithelium stratification in 3-day sections, diffused hyperplasia, vast hyperplasia plaque and solid bubbles in 6-day sections (P < 0.05), aggragated fibrilblasts and capillary endothelium hyperplasia and formation of large amount of solid sequential follicles in 9-day sections, mass hollow sequential follicles in 12-day sections. PAS staining showed weak positive in 3-day, 6-day, 9-day thyroid gland follicle colloid sections, and negative in 12-day sections. A coherent of changes with time was observed in PCNA labeling index and PCNA/beta-actin ratio, i.e. starting to increase in 3-day group (P < 0.05), reaching its peak at 6-day group (P < 0.05) and decreasing from 9-day group (P < 0.05), while no significant difference comparing with control in 12-day group.. Hyperplastic patch, solid bubble and PCNA labeling index detected by IHC used as early index for thyroid gland hyperplasia are stable and relient, and 6 day is optimization experiment phase.

Topics: Animals; Antithyroid Agents; Dose-Response Relationship, Drug; Hyperplasia; Male; Proliferating Cell Nuclear Antigen; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyroid Gland; Thyroid Hormones; Thyrotropin; Thyroxine; Time Factors; Triiodothyronine

To study the expression rule of proliferating cell nuclear antigen (PCNA) in thyroid when the hyperplasia of male rat thyroid is induced by propylthiouracil (PTU).. PTU was administered to rats by gavage at a dose of 5.0 mg/kg B. W for 0,3,6,9 and 12 days respectively. All animals were sacrificed after the last dosage, and the expression of PCNA in thyroid was detected by immunohistochemistry and RT-PCR.. Compared with the control group, the PCNA level in the thyroid of rats given PTU for 3 days significantly increased (P < 0.05),and reached the highest expression when it was 6 days, but then when it was 9 days and 12 days, the PCNA expression showed a descending tendency.. PCNA has a expression rule in hyperplastic thyroid: expression increase first but then decrease. This rule confirms the histological change of thyroid in earlier stage. The experimental time of assessment test to thyroid hormone disruptors will be shortened to six days.

Topics: Animals; Antithyroid Agents; Hyperplasia; Male; Proliferating Cell Nuclear Antigen; Propylthiouracil; Rats; Thyroid Gland

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 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

Reports of the coexistence of hyperparathyroidism and thyroid disease have raised the issue of a possible etiologic relationship. The present study tests the hypothesis that chronic elevation of thyroid-stimulating hormone (TSH) is related to the development of hyperparathyroidism. Four groups of 60 female rats were treated as follows: group 1, control; group 2, propylthiouracil (PTU) 0.0025%; group 3, PTU 0.0025% plus thyroxine, 5 microg two times per week; and group 4, only thyroxine. The animals' serum calcium, phosphorus, TSH, thyroxine, and parathyroid hormone (PTH) levels were evaluated at 0, 6, 12, and 18 months. Significant elevation of TSH was sustained throughout the 18 months in groups 2 and 3. The PTH levels were also significantly elevated in both group 2 and group 3 animals (P = 0.02). The histopathologic features of the parathyroids were evaluated at 18 months. In the group 2 (PTU only) animals, which had profound hypothyroid, 44% developed parathyroid adenomas. In the group 3 (PTU plus thyroxine) animals, who had mildly elevated TSH levels, 53% developed parathyroid adenomas. These findings are consistent with the hypothesis that prolonged TSH stimulation may lead to hyperparathyroidism in the rat model.

Topics: Adenoma; Animals; Antithyroid Agents; Calcium; Chronic Disease; Disease Models, Animal; Female; Hyperparathyroidism; Hyperplasia; Hypothyroidism; Parathyroid Glands; Parathyroid Hormone; Parathyroid Neoplasms; Phosphorus; Propylthiouracil; Rats; Rats, Sprague-Dawley; Survival Rate; Thyroid Gland; Thyrotropin; Thyroxine

Forty-three 8-week-old male Wistar rats were studied to evaluate temporal changes of transforming growth factor beta1, (TGF-beta1) mRNA levels in thyroid tissue during pharmacologically induced goiter. Four rats were treated with purified bovine thyrotropin (TSH; Ambinon, 2 mU/day sc) for 7 days before being sacrificed. Thirty-one were treated with propylthiouracil (PTU), added to their drinking water at a concentration of 0.2 g%, and subsequently were sacrificed as follows: five after 1 week (PTU-1): five after 2 weeks (PTU-2); five after 4 weeks (PTU-4); five after 8 weeks (PTU-8); five after 12 weeks (PTU-12). In six rats, after 12 weeks of treatment. PTU was withdrawn for 2 months and subsequently started again in three rats which were sacrificed after 2 weeks (PTU-R); the remaining three rats were sacrificed without any further treatment (PTU-R control). Eight rats (control rats) were never treated and served as controls. After sacrifice, blood was drawn for determination of total thyroxine and the thyroid was excised and subdivided into two lobes. Northern analysis for TGF-beta1 was performed in one lobe. while histological and immunohistochemical studies were performed in the other lobe. Gene expression of TGF-beta1 was induced in TSH- and PTU-treated rats. In TSH-treated rats TGF-beta1 gene expression was less detectable than in PTU-treated rats, where it became evident after 2 weeks and remained through weeks 4-8. Gene expression of TGF-beta1 wits also seen in PTU-R rats, but not in the control and in the PTU-R control. Immunohistochemical analysis showed a different presence and location for the TGF-beta1 protein, which appears to be dependent on the time of exposure to mitogenic stimulus. In conclusion, TGF-beta1 is produced in response to both a direct (TSH by itself) and indirect (TSH induced by PTU-induced hypothyroidism) cellular proliferative stimulus and is not linked to an adaptative phenomenon secondary to hypothyroidism. The immunohistochemical location of TGF-beta1 within the thyrocytes is influenced by mitogen exposure time. A TGF-beta1 immunohistochemical evaluation may be important to define exposure time and activity of goitrogenic stimuli.

Topics: Animals; Blotting, Northern; Cattle; Goiter; Hyperplasia; Male; Propylthiouracil; Rats; Rats, Wistar; RNA, Messenger; Thyroid Gland; Thyrotropin; Time Factors; Transforming Growth Factor beta

The coexistence of hyperparathyroidism and thyroid tumors and/or chronic thyroiditis has raised the possibility of an etiologic relationship. The present study was designed to test the hypothesis that the chronic elevation of thyroid-stimulating hormone (TSH) is related to the development of hyperparathyroidism. Three groups of 24 rats each were treated for 12 weeks as follows: group 1 received propylthiouracil (PTU) in their deionized water; group 2 received PTU and thyroid hormone to suppress TSH and to serve as a control group for possible direct effects of PTU; and group 3 was not treated at all and served as another control group. At 12 weeks, 95% of group 1 rats (PTU only) showed hyperplasia of the parathyroids with a 30% mean increase in circulating parathormone.

Topics: Administration, Oral; Animals; Calcium; Delayed-Action Preparations; Drug Implants; Female; Hyperparathyroidism; Hyperplasia; Hypothyroidism; Parathyroid Glands; Parathyroid Hormone; Phosphorus; Propylthiouracil; Rats; Rats, Sprague-Dawley; Thyroid Gland; Thyrotropin; Thyroxine

Estrogen receptor (ER) levels were evaluated in thyroid tumors induced by N-methyl-N-nitrosourea (MNU) and low iodine diet (LID) or propylthiouracil (PTU) in intact and estrogen (E2) loaded Long-Evans (LE) rats. MNU at 40 mg/kg body wt was injected in 50 day-old LE rats of both sexes. The animals were killed 17-22 weeks later and the thyroid tissues were subjected to ER assay. In LID-treated groups, cytosolic ER (cER) levels were 6.7 +/- 5.8 (fmol/mg protein, mean +/- SE) in females and 0.7 +/- 1.4 in males, E2 increased the ER levels. In E2-loaded LID groups, cER levels were 12.9 +/- 3.7 in females and 1.7 +/- 1.7 in males. PTU treatment produced almost comparable ER levels as LID treatment. PTU treatment as well as LID treatment increased the serum TSH levels with E2 treatment producing additional elevation. In evaluating ER levels by histological type of thyroid tumors, the level in cER plus nER showed the lowest value of 6 +/- 6.4 (fmol/mg DNA, mean +/- SE) in hyperplasia, followed by 129 +/- 52.3 in adenoma and 289 +/- 51.7 in carcinoma. The rates of BrdU incorporation in thyroid follicles indicated higher proliferation activity in the area of adenoma and carcinoma rather than in the hyperplastic area. These data suggested that E2 treatment increases the ER levels in MNU and LID/PTU-induced thyroid tumors. The level of ER was correlated to the histological type of thyroid tumors.

Topics: Adenoma; Animals; Carcinoma; Estrogens; Female; Hyperplasia; Iodine; Male; Methylnitrosourea; Organ Size; Pituitary Gland; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Estrogen; Thyroid Gland; Thyroid Neoplasms; Thyrotropin

In the present study, changes in thyroid follicular cell volume and its regulation have been investigated during the early involution of a hyperplastic goitre. Male Wistar rats were administered an iodine deficient diet for 6 months with propylthiouracil (PTU, 0.15%) during the last two months. At the end of iodine deficiency (day 0), some rats were killed and the others received a normal iodine diet. These rats were killed after different periods of iodine refeeding. Thyroid follicular cell volume was very high in hyperplastic gland whereas thyroid protein concentration was low. Thyroid follicular cell volume quickly decreased when rats were normally iodine refed, whereas thyroid protein concentration increased. Electron microscopal observations showed that thyroid follicular cells retained their endocrine aspect in hyperplastic state and throughout the iodine refeeding period. Using concomitant stereological and biochemical techniques, it is shown that the amount of cellular iodide and an unknown iodinated compound strongly increased during the early iodine refeeding. Plasma TSH was high on day 0 and remained at this level until day 8 whereas plasma T3 and T4 were low on day 0 and remained at this low level until day 4. The present data show that the involution of thyroid follicular cell volume is induced by iodide and mediated by an iodinated compound at least in the initial phase, and is independent of plasma TSH, T3, T4, so indicating the involvement of a thyroid autoregulatory mechanism. These changes in cell volume may be of importance in ion transport, i.e. in the metabolism of thyroid follicular cell during the early involution of the hyperplastic goitre.

Topics: Animals; Down-Regulation; Hyperplasia; Iodides; Iodine; Iodine Radioisotopes; Male; Microscopy, Electron; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Neoplasms; Thyrotropin; Thyroxine; Triiodothyronine

Hyperplasia of the thyroid gland induced by propylthiouracil (PTU) is a well established model of rapid cell proliferation in vivo. Recent evidence indicates that tyrosine kinase activity is associated with growth factor receptors and oncogene protein products and may have an important regulatory action in the control of cell growth. Thus, we examined tyrosine kinase activity in rat thyroid membrane and cytosol preparations at rest and during PTU-induced hyperplasia. Although kinase activity was present in a crude microsomal membrane preparation, no change was observed during thyroid growth. In contrast, tyrosine kinase activity assayed with the artificial substrate poly(Glu,Na:Tyr) 4:1 was present in normal rat thyroid cytosol and increased 2- to 6-fold during the rapid phase of hyperplasia in the first 5-10 days of PTU treatment. It declined to control values by day 15, when the size and DNA content of the thyroid reached a plateau. Preincubation of the cytosolic preparations with several peptides known to bind to and activate growth factor receptor tyrosine kinases failed to enhance the activity, suggesting, along with the cytosolic localization, that the activity was distinct from these receptors. By gel filtration chromatography and polyacrylamide gel electrophoresis, tyrosine kinase activity was associated with a 55 kDa protein. Partial purification over a poly(Glu,Na:Tyr)4:1-Sepharose column, yielded a protein that appeared capable of autophosphorylation. It is suggested that this tyrosine kinase plays a role in mediating the growth-promoting effects of this model of thyroid cell hyperplasia.

Topics: Animals; Cell Division; Cell Membrane; Chromatography, Gel; Cytosol; Histones; Hyperplasia; Kinetics; Male; Molecular Weight; Phosphopeptides; Phosphorylation; Propylthiouracil; Protein-Tyrosine Kinases; Rats; Rats, Inbred Strains; Receptors, Somatotropin; Thyroid Gland

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

The aim of this work was to investigate some aspects of the thyroid epithelial cell kinetics during the iodide-induced involution of a hyperplastic goitre in the rat. Rats were made iodine-deficient for 6 months, and propylthiouracil (PTU) (0.15%) was added to the diet during the last 2 months. Thereafter, rats were refed with iodide and PTU was removed (day 0). Forty-eight hours previously, all the rats were injected with tritiated thymidine ([3H]TdR) (1 microCi/g). Some animals were killed 1 hr or 24 hr after [3H]TdR injection (i.e. on day -2 and -1, day 0 corresponding to the restoration of a normal iodine diet); the other animals were killed after different delay periods and following [3H]TdR injection. Autoradiography of thyroid sections, iodine determination of plasma iodide and protein-bound iodine (PBI), and RIA of plasma thyroid stimulatory hormone (TSH) were performed. Plasma TSH concentration was very high on day 0 of iodide refeeding (3000 +/- 330 ng/ml) and remained at this level until day 8. Plasma PBI was very low on day 0, remained so until day 4 and greatly increased on day 8. Plasma iodide was also very low on day 0, but markedly increased on day 1, then did not vary significantly until day 43 of iodine refeeding. Thyroid weight, elevated on day 0, decreased relatively quickly until day 30, then more slowly until day 73. The [3H]TdR labelling index (LI) of the thyroid epithelial cells (TEC) was high on day 0 (56 +/- 3 labelled cells/10,000 cells), and 24 hr thereafter increased to 104 +/- 3, by division of the labelled cells. On day 1 of iodine refeeding, the LI had abruptly decreased to about half this value and then remained stable for 3 more days. Between day 4 and day 16, a progressive decline in the LI, (by about 3-4 per day), was observed. The LI showed no further modification, up to day 73, the longest period investigated. The decrease in LI occurred without any significant changes in the labelling intensity (grain count) of the remaining labelled cells between day 1 and 16, this indicates that no cell division took place during this period. The data are therefore interpreted as showing a biphasic elimination after iodide refeeding, of cells that were actively proliferating during the goitrous state.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Animals; Cell Division; Diet; Epithelium; Goiter; Hyperplasia; Iodine; Male; Propylthiouracil; Rats; Rats, Inbred Strains; Thyroid Function Tests; Thyroid Gland; Thyrotropin

We have observed that membranes isolated from rat thyroids contain receptors for the insulin-like growth factors (IGF). As IGFs are known to be important mediators of tissue growth, we conducted this study to determine whether modulation of thyroid IGF receptors might be involved in TSH-stimulated hyperplasia. A substantial increase in both the weight of the thyroid and its DNA content was observed within 2 days of exposing adult male rats to 0.1% propylthiouracil (PTU) in their drinking water. Serum T4 reached unmeasurable levels and serum TSH rose 3-fold over control by the tenth day of treatment. [125I]Iodo-human(h)IGF-II binding to membranes isolated from hyperplastic glands was significantly higher than control beginning at 2 days. A maximum was reached after 5 days (13.3 +/- 0.8%/25 micrograms protein vs. a control level of 6.7 +/- 0.7%, mean +/- SEM). The increase had disappeared by 15 days of PTU exposure, paralleling the drastic fall in the growth rate of the glands. This increase in binding was specific for the thyroid, as it was not seen in other organs. In both treated and control animals, the receptor involved was shown to be type II by preferential binding to IGF-II, lack of interaction with insulin, and molecular sizing. The observed increase in binding could be accounted for by an increase in receptor site number, the affinity remaining essentially the same. We conclude that the TSH-stimulated hyperplasia of the rat thyroid, induced by PTU, is associated with an increase in the binding sites of the type II IGF receptor. This observation raises the possibility that modulation of this receptor may play a role in the mediation of the mitogenic effect of TSH on the thyroid gland.

Topics: Animals; Electrophoresis, Polyacrylamide Gel; Hyperplasia; Insulin-Like Growth Factor I; Male; Membranes; Propylthiouracil; Rats; Rats, Inbred Strains; Receptors, Cell Surface; Receptors, Somatomedin; Thyroid Gland

Delayed morphological changes induced in mouse hyperplastic thyroid by refeeding iodine were analyzed by light and electron microscopy, stereology, and autoradiography. Thyroid hyperplasia was induced by a low iodine diet supplemented with 0.25% propylthiouracil for 10 days. Involution was obtained by discontinuing the propylthiouracil and returning either to a moderate iodine diet [(MID) 1 microgram I/day] or to an iodine-rich diet [(HID) 10 micrograms I/day] for 40 days. In other experiments, three cycles of hyperplasia (8 days) and subsequent involution (8 days) with MID or HID were brought about. Control animals were fed MID or HID. All animals were killed when 12-14 weeks old after injection of 10-50 microCi 125I. Double labeling, with repeated injections of [3H]thymidine from day 0 to day 7 of involution followed by 125I injection 4 h before killing, was also performed. When involutions were performed with MID, most morphological variables returned to control values. However, when involution was brought about with HID, the glandular weight, the number of follicles, and the relative volume of follicular lumina remained larger than in controls. Moreover, the 125I-labeling pattern of the follicles was altered. The proportions of unlabeled, and unevenly or partly labeled, follicles, which were fewer than 5% in control groups, represented 25-35% of all follicles after involution with HID, whereas they were unchanged with MID. In unlabeled follicles the epithelium was flattened, with a reduced number of microvilli. Partly labeled follicles were of two types. In some follicles a persistent ring reaction was observed, suggesting an abnormally slow mixing of thyroglobulin. In others, the 125I labeling was restricted to areas adjacent to the apex of a reduced number of cells, suggesting that some cells were iodinating thyroglobulin, whereas others were not. There was no relationship between the follicular 125I labeling and the frequency of [3H]thymidine-labeled cells. These results indicate that refeeding iodine excess after hyperplasia leads to the formation of a colloid goiter with new follicles, and to an increased heterogeneity of iodine metabolism among follicles and among cells.

Topics: Animals; Cytoplasm; Endoplasmic Reticulum; Epithelium; Female; Goiter; Hyperplasia; Iodine; Mice; Mice, Inbred C3H; Microscopy, Electron; Microvilli; Organ Size; Propylthiouracil; Thyroid Gland

Measurement of total DNA, RNA, and protein as well as weight of the heart in male rats at 10, 25, 50, and 90 postnatal days revealed that hypothyroidism, as induced by administration from birth of the goitrogen propylthiouracil (PTU), results in highly significant reductions in cardiac cell proliferation and cell growth. These inhibitory effects on hyperplastic and hypertrophic growths were less drastic during the suckling period than during the postweaning period. In the latter period, heart growth of the hypothyroid animals was found to remain at a standstill with regard to all the parameters measured. When, after 25 days of hypothyroidism, PTU treatment was discontinued, the retarded heart showed marked signs of rehabilitation and compensatory development. Indeed, by day 90, total DNA content had essentially compensated for its deficit but total RNA, protein content, and weight, though showing marked compensatory surges (from 80-90% deficit to 20-30%), were not yet fully compensated. The results clearly indicate that the growing heart has a marked ability to be rehabilitated from severe hypothyroid retardation, showing within 2 mo full compensation of cell number and nearly complete compensation of cell growth. It is suggested that rehabilitation of the heart is brought about by physiological restoration not only of the thyroid hormones but also of growth hormone and possibly other thyroid-dependent growth factors.

Topics: Animals; Animals, Newborn; Cell Division; DNA; Heart; Hyperplasia; Hypothyroidism; Male; Myocardium; Organ Size; Propylthiouracil; Proteins; Rats; RNA; Thyroid Hormones; Time Factors

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

Involution of thyroid hyperplasia was induced in C3H mice by discontinuing a goitrogenic treatment (low iodine diet supplemented with 0.25% propylthiouracil) and refeeding a normal iodine diet. Thyroid involution was studied by morphological, histochemical, autoradiographic, and stereological methods. The onset of the involution was characterized by an early accumulation of colloid, the presence of necrotic cells in the follicular lumina, and the appearance of homogeneous microcavities in the epithelial layers. The intraepithelial microcavities had the same morphological and functional properties as the follicular lumina. They were limited by a membrane covered with microvilli; polysaccharides and peroxidase activity were detected on their membranes, and 125I-labeling was marked in their lumina. Thin serial sections demonstrated that the microlumens originated from the intercellular space; plasma membranes differentiated into junctional complexes, and a narrow lumen limited by a membrane covered with short microvilli was formed in the intercellular space between the junctions. Later on, the newly formed microlumens fused to form new follicles with a cloverleaf pattern. As a consequence of the folliculogenesis, the total number of follicles doubled after 8 days of involution. This increase in number was mainly due to the presence of a population of small follicles. The folliculogenesis was associated in the first 4 days of involution with an active cellular multiplication which compensated for the early cell necrosis and led to a doubled number of epithelial cells. The increase in the total number of follicles and cells could partially explain the persistence of a relatively high thyroid weight after involution of hyperplasia.

Topics: Animals; Female; Hyperplasia; Iodine; Mice; Mice, Inbred C3H; Propylthiouracil; Thyroid Gland; Time Factors

Topics: Animals; Female; Hyperplasia; Male; Molecular Weight; Nucleic Acid Hybridization; Poly A; Polyribosomes; Propylthiouracil; Protein Biosynthesis; Rats; RNA, Messenger; RNA, Ribosomal; Thyroglobulin; 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; Centrifugation, Zonal; Diet; Hyperplasia; Iodides; Iodine; Iodine Radioisotopes; Propylthiouracil; Rats; Thyroglobulin; Thyroid Gland; Thyrotropin; Thyroxine

Topics: Animals; Cell Count; Cytochrome Reductases; DNA; Enzyme Induction; Hyperplasia; Iodine; Kinetics; Male; Organ Size; Peroxidases; Propylthiouracil; Rats; Thyroid Diseases; Thyroid Gland; Thyrotropin

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

Topics: Animals; Deficiency Diseases; Diet; Disease Models, Animal; Estradiol; Hyperplasia; In Vitro Techniques; Injections, Intramuscular; Iodine; Mammary Glands, Animal; Propylthiouracil

Topics: Animals; Colloids; Cricetinae; Disease Models, Animal; Goiter; Hyperplasia; Iodine; Male; Microscopy, Electron; Propylthiouracil; Thyroglobulin; Thyroid Hormones; Thyrotropin

Topics: Animals; Deficiency Diseases; Feedback; Goiter; Hyperplasia; Iodine; Iodine Isotopes; Iodoproteins; Male; Perchlorates; Propylthiouracil; Rats; Thyroid Hormones; Thyrotropin

Topics: Animals; Colloids; Deficiency Diseases; Diet; Female; Goiter; Hyperplasia; Iodine; Male; Organ Size; Propylthiouracil; Rats; Thyroglobulin; Thyroid Gland; Thyrotropin

Topics: Animals; Animals, Newborn; Female; Fetus; Guinea Pigs; Hyperplasia; Maternal-Fetal Exchange; Pituitary Gland; Pregnancy; Pregnancy, Animal; Propylthiouracil; Thyroid Gland; Thyrotropin; Thyroxine; Triiodothyronine

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

Topics: Guinea Pigs; Hyperplasia; Iodides; Iodine; Iodine Radioisotopes; Propylthiouracil; Thiouracil; Thyroid Gland