methimazole and Hyperplasia

We report here a case of a paediatric hyperthyroidism due to a micro-macro-follicular thyroid adenoma in the presence of heterozygous point mutation of TSH receptor (TSHr). We describe the case from the initial diagnosis, through laboratoristic examinations and imaging techniques, until the radical surgical treatment made by a mini-cervicotomic videoassisted technique. We also explained the genetic work-up from peripheral blood and thyroid adenoma tissue.

Topics: Adenoma; Amino Acid Substitution; Exons; Hormone Replacement Therapy; Humans; Hyperplasia; Hyperthyroidism; Infant, Newborn; Male; Methimazole; Mutation, Missense; Receptors, Thyrotropin; Thoracic Surgery, Video-Assisted; Thyroid Neoplasms; Thyroid Nodule; Thyroidectomy; Thyroxine

Benign thymic hyperplasia (TH) is a known feature of hyperthyroidism. In most cases, thymic enlargement is minimal; however, this syndrome may occasionally appear as an appreciable anterior mediastinal mass. Recognition of the benign nature of TH and its regression following treatment of the hyperthyroidism is important to prevent unnecessary surgical procedures. We present a case of TH associated with hyperthyroidism due to Graves' disease.

Topics: Animals; Antithyroid Agents; Diagnosis, Differential; Female; Graves Disease; Humans; Hyperplasia; Immunoglobulins, Thyroid-Stimulating; Indium Radioisotopes; Magnetic Resonance Imaging; Mediastinal Neoplasms; Methimazole; Radionuclide Imaging; Receptors, Thyrotropin; Somatostatin; Thymic Factor, Circulating; Thymoma; Thymus Gland; Thymus Neoplasms; Young Adult

To assess the involvement of cellular inhibition and the appearance of apoptosis in regression of the hyperplastic thyroid gland towards normality, an experimental design was used to elicit non-toxic goiter by inducing hyperplastic goiter in rats by treatment with methimazole. We performed a morphological and PCNA immunocytochemical study together with in situ end labelling with bromodeoxyuridine in thyroid glands of rats receiving methimazole in their drinking water over 21 days after which they were allowed a recovery period of 0, 12, 24, 36, 48 and 72 h and 7, 14, 21 and 44 days. Serum T3 and T4 levels were found to be very low in the methimazole-treated animals although they increased after the goitrogenic compound had been withdrawn. Inhibition of cell proliferation and the burst of apoptosis play important roles in the regression of hyperplastic goiter in rats. Cell proliferation, which was strongly stimulated during goiter, fell significantly at 24 h, thereafter decreasing gradually as the recovery period progressed. Isolated cases of thyrocyte necrosis were observed ultrastructurally. Light and transmission electron microscopy revealed the existence of thyroid apoptosis with respect to the development of the study over time. Most apoptotic thyrocytes became detached from the follicular epithelium and later underwent cellular degeneration in the follicular lumen. The remaining apoptotic cells retracted their cytoplasm, lost contact with the follicular lumen and became located at the base of the follicles. The percentage of apoptosis showed that during the first week of thyroid involution apoptosis was already present but with low percentages while maximum values were attained at 21 days of survival. Our results suggest that, in the rat, during the return of thyroid follicular cells to normality after methimazole-induced hyperplastic goiter a balance arises between proliferation and cell death and that this balance is due to the inhibition of cellular proliferation and, secondarily, to the appearance of apoptosis, which becomes particularly evident towards the end of the first week after withdrawing the goitrogenic agent.

Topics: Animals; Antithyroid Agents; Apoptosis; Bromodeoxyuridine; Cell Division; Epithelial Cells; Female; Goiter; Hyperplasia; Immunoenzyme Techniques; In Situ Nick-End Labeling; Male; Methimazole; Proliferating Cell Nuclear Antigen; Rats; Rats, Sprague-Dawley; Thyroid Gland; Thyroxine; Triiodothyronine

Administration of a goitrogen (methimazole) and a low iodine diet to rats over a two-week period resulted in hypothyroidism and thyroid hyperplasia compared with controls (control: total serum thyroxine (T4) 66 +/- 4 nmol/l, thyroid weight 5 +/- 1 mg/100 g body weight; experimental: T4 undetectable, thyroid weight 27 +/- 4 mg/100 g body weight after 2 weeks of treatment; mean +/- S.D., n = 10). Immunohistochemistry carried out using a specific endothelial cell marker, CD31, and morphometric analysis (point counting of immunopositive cells) revealed that the progression of goitre in the rat thyroid is accompanied by an increase in capillary endothelial cell growth (neovascularisation). Fibroblast growth factor-2 (FGF-2) immunohistochemistry revealed widespread staining for the protein in the follicular cells of control glands. Less intense staining was found in the stroma and follicular cell nuclei. During hyperplasia and subsequent neovascularisation there was a progressive increase in the FGF-2 immunoreactivity at all locations during the two-week treatment period. Thrombospondin-1 (TSP1) immunoreactivity in the control rat thyroid was found in the stroma and in the endothelial cells, while weak follicular cell staining was also present. In the goitrous rat thyroid the TSP immunoreactivity was present after 1 week of treatment in the endothelial cells and most follicular cells, whilst stroma localisation was weak. After week 2 of treatment the endothelial cell and stromal localisation was no longer apparent, although a follicular localisation was still present. Transforming growth factor-beta 1 (TGF beta 1) immunoreactivity was present in the cytoplasm of a minority of the follicular cells in control rat thyroids, while their nuclei were unstained. In the goitrous rat thyroid an increase intensity of staining for TGF beta 1 was seen in all follicular cells, many of which now also demonstrated immuno-positive nuclei, within one week of goitrogen administration. These results show that in the hyperplastic thyroid increases in FGF-2 and TGF beta 1, and decreases in TSP1 accompany angiogenesis. These factors may interact in an autocrine/paracrine relationship to stimulate the neovascularisation that occurs during goitre formation.

Topics: Animals; Cell Adhesion Molecules; Cytoplasm; Endothelium; Fibroblast Growth Factor 2; Goiter; Growth Substances; Hyperplasia; Immunohistochemistry; Male; Membrane Glycoproteins; Methimazole; Neovascularization, Pathologic; Rats; Rats, Inbred Strains; Thrombospondins; Thyroid Gland; Transforming Growth Factor beta

We have investigated changes in the synthesis and localization of insulin-like growth factor (IGF)-I and IGF binding proteins (IGFBPs) in thyroid tissues during the induction of goitre in iodine-deficient rats, and during the subsequent involution of the gland following goitrogen withdrawal. Goitre was induced in adult rats by acute (1 or 2 weeks) or chronic (4 or 10 weeks) administration of methimazole together with a low iodine diet. After twelve weeks the goitrogenic stimuli were removed and thyroids examined 4 weeks later. Circulating T4 levels became undetectable within two weeks of goitrogen administration while thyroid weight had increased five-fold. The thyroids continued to increase in size up to 10 weeks, but at a slower growth rate. IGF-I mRNA, detected by ribonuclease protection assay, was present in the control rat thyroid and increased in abundance after both 1 and 2 weeks of goitrogen administration. Levels of IGF-I mRNA showed a relative decline with prolonged goitrogen administration, and following thyroid involution the hybridization signal was similar to that seen in control glands. Northern blot hybridization showed that IGFBP-2, -3 and -5 mRNAs were all present in growth-quiescent, control thyroids and those encoding IGFBP-2 and -3 were elevated in the goitrous glands and remained so as long as goitrogen was administered, thereafter declining during thyroid involution. IGF-I and IGFBP-2 and -3 mRNAs and synthesized peptides, detected by in situ hybridization and immunohistochemistry respectively, were found to co-localize predominantly in follicular epithelial cells. IGFBP-5 mRNA abundance was unaltered during goitre formation, but was increased in the involuting thyroid. Both IGFBP-5 mRNA and peptide were localized to the parafollicular cells (C-cells) which were increased in number during involution. The results suggest that an increased expression of IGF-1 may contribute to early goitre formation, but that a relative increase in the abundance of IGFBP-2 and -3 may limit IGF availability at later times, and facilitate a slowing of thyroid growth rate. The discrete expression of IGFBP-5 by C-cells suggests that it could contribute indirectly to goitre formation or involution by acting in a paracrine fashion.

Topics: Animals; Carrier Proteins; Gene Expression Regulation, Neoplastic; Goiter; Hyperplasia; Hypertrophy; Immunoenzyme Techniques; In Situ Hybridization; Insulin-Like Growth Factor Binding Protein 5; Insulin-Like Growth Factor I; Male; Methimazole; Rats; Rats, Wistar; RNA, Messenger; Thyroid Gland; Thyroxine

Four hundred and fifty two patients having clinical features of thyrotoxicosis have been studied for their hormonal (T4, T3 and TSH) content, I131 uptake levels and FNAB at repeated intervals. Four hundred and twenty seven had presented with diffuse enlargement and rest 25 cases with nodular enlargements. Of the primary hyperthyroidism cases 342 (82.4%) were of Grave's disease without exophthalmos and 73 (17.6%) with exophthalmos. T4, T3 and I131 uptake levels have correlated well with the degree of morphological changes as observed on FNAB. Degree of nuclear pleomorphism has correlated well with the duration of disease. Critical evaluation of morphological changes on FNAB has been done in all cases of primary hyperthyroidism being treated with neomercazole and radioactive iodine therapy. Treatment with neomercazole had shown, good correlation between time lag and the retrogressive changes. This was not so in cases treated with radioactive iodine therapy. Various known complications of radioactive treatment e.g. development of hypothyroidism, refractory and recurrent hyperthyroidism, exacerbation of the disease, radiation thyroiditis, and severe degree of dysplastic changes could be demonstrated in some cases on serial aspirations.

Topics: Biopsy, Needle; Female; Humans; Hyperplasia; Hyperthyroidism; Iodine Radioisotopes; Male; Methimazole; Thyroid Hormones; Thyrotoxicosis

Cyclic AMP (cAMP) is the major intracellular second messenger of thyrotropin (TSH) action on thyroid cells. It stimulates growth as well as the function and differentiation of cultured thyrocytes. The adenosine A2 receptor, which activates adenylyl cyclase via coupling to the stimulating G protein (Gs), has been shown to promote constitutive activation of the cAMP cascade when transfected into various cell types. In order to test whether the A2 receptor was able to function similarly in vivo and to investigate the possible consequences of permanent adenylyl cyclase activation in thyroid cells, lines of transgenic mice were generated expressing the canine A2 adenosine receptor under control of the bovine thyroglobulin gene promoter. Thyroid-specific expression of the A2 adenosine receptor transgene promoted gland hyperplasia and severe hyperthyroidism causing premature death of the animals. The resulting goitre represents a model of hyperfunctioning adenomas: it demonstrates that constitutive activation of the cAMP cascade in such differentiated epithelial cells is sufficient to stimulate autonomous and uncontrolled function and growth.

Topics: Adenosine; Animals; Blotting, Northern; Brain; Cattle; Cell Membrane; Cyclic AMP; Dogs; Hyperplasia; Hyperthyroidism; Kinetics; Methimazole; Mice; Mice, Transgenic; Phenethylamines; Poly A; Promoter Regions, Genetic; Receptors, Purinergic; Receptors, Thyrotropin; Reference Values; RNA; RNA, Messenger; Thyroglobulin; Thyroid Gland; Thyroxine; Triiodothyronine

By means of morphological, morphometrical and autoradiographical methods restorative processes in the parathyroid glands in 41 euthyroid and in 41 hypothyroid rats have been studied during 1-24 days after mechanical trauma of the glands or after hemithyroparathyroidectomy. Seven hypothyroid and 7 euthyroid rats serve as a control. Hypothyroidism is produced with daily injection of mercazolil (6 mg/kg) 3 weeks before the operation and during the time of the experiment. In nonoperated hypothyroid rats development of hypertrophy in parathyrocytes is noted. Prolonged injection of mercazolil weakens (posttraumatic regeneration) or completely suppresses (compensatory hypertrophy) mitotic activity of the glandular cells (in comparison with the euthyroid animals). Manifestation of hypertrophy in parathyrocytes of the hypothyroid rats in comparison with the corresponding control is also less, than against the background of euthyreosis.

Topics: Animals; Hyperplasia; Hypertrophy; Hypothyroidism; Male; Methimazole; Mitosis; Parathyroid Glands; Rats; Thyroidectomy

Sixty Fischer 344 rats were fed a diet containing 90 ppm methimazole, a known antithyroid compound. Following exposure to the test compound, groups of ten animals were terminated at 1, 3, and 6 months. Similar groups of ten treated animals were given control diet for a reversibility period of 2, 3, and 6 months, respectively. Groups of ten control rats were terminated after 1, 3, 6, and 12 months. Except for the expected effect on body weight, the treated animals had no physical signs of toxicity. The weight of thyroids increased with the duration of exposure, becoming in males after 6 months about ten times the weight of thyroids from control rats. Thyroids of treated rats after 1 and 3 months had a diffuse homogeneous hypertrophy and hyperplasia of follicular cells, decreased colloid, and increased vascularity. After 6 months' exposure to the antithyroid compound, there was diffuse hyperplasia but also a heterogeneity in the size and morphology of follicles, protrusion of follicular tissue through the gland capsule and into vascular spaces, and the development of follicular nodules. Treated rats placed on control diet, allowing for reversibility, had thyroids which were decreased in size with large follicles and flattened epithelium, and a complete remodeling of most nodules with no evidence of progression. Although the nodules produced after prolonged administration of the antithyroid compound had many of the characteristics of neoplasia, the biologic behavior supports the diagnosis of nodular hyperplasia.

Topics: Animals; Cell Division; Female; Hyperplasia; Male; Methimazole; Organ Size; Rats; Rats, Inbred F344; Thyroid Gland; Time Factors

"Autoimmune" hypoglycemia is a syndrome consisting of fasting hypoglycemia, hyperinsulinemia, and insulin-binding antibodies in a patient who has never been exposed to exogenous insulin. The stimulus for insulin-antibody formation and the mechanism of the hypoglycemia in this condition remain unknown. Three patients with this rare syndrome had severe hypoglycemia of limited duration. Two had received a drug containing a sulfhydryl group (methimazole and penicillamine) as treatment for an autoimmune disorder (Graves' disease and rheumatoid arthritis, respectively). A third patient who underwent surgery for a suspected insulinoma was found to have pancreatic beta cell hyperplasia. Drugs containing a sulfhydryl group may have a role in the etiology of the syndrome. Additionally, our findings suggest a relationship between circulating insulin antibodies and beta cell hyperplasia.

Topics: Autoantibodies; Diagnosis, Differential; Female; Humans; Hyperplasia; Hypoglycemia; Insulin Antibodies; Insulinoma; Islets of Langerhans; Male; Methimazole; Middle Aged; Pancreatic Neoplasms; Penicillamine; Syndrome

When rats are treated by an antithyroid drug as the thiamazole, an hyperplasia of the parafollicular thyroideal cells can occur during the treatment, as shown in our previous works, or not, as in the present experiment. This difference depends on the dose of drug used, but it both cases parafollicular tumours never appear during this treatment. Whatever was the initial reaction of the parafollicular cells during the treatment, an important hyperplasia of these cells always expands after its stop and is frequently followed by the development of parafollicular tumours. Then, the initial hyperplasia sometimes obtained is not prerequisite for the formation of neoplasm. The mechanism of tumoral formation must be investigated in the disorders which follow the stop of the treatment.

Topics: Animals; Antithyroid Agents; Hyperplasia; Male; Methimazole; Rats; Thyroid Gland; Thyroid Neoplasms; Time Factors

The nature of tumors appearing in the thyroid gland and in the lungs of mice fed two standard goitrogenic drugs (MTU and MII) has been studied. These tumors have been considered malignant on the basis of their morphological appearance and their occurrence in abnormal locations. Some investigatiors, however, have questioned that they are actually malignant. The present results indicate that these tumors are most likely not malignant even if it is shown that the pulmonary nodules are of thyroid origin. The thyroid adenomas disappear once the goitrogen is withdrawn, but thryoid enlargement pesists, and event 6 months after discontinuation of the goitrogenic treatment , pulmonary nodules are still produced. Evidence is presented that these nodules are emoli from hyperplastic thyroid tissue and not tumors.

Topics: Adenoma; Animals; Carcinoma, Hepatocellular; Diet; Glycolysis; Hyperplasia; Iodine; Liver Neoplasms; Lung Neoplasms; Male; Methimazole; Methylthiouracil; Mice; Mice, Inbred Strains; Oxygen Consumption; Thyroid Gland; Thyroid Neoplasms

Topics: Adenocarcinoma; Adenoma; Animals; Female; Hyperplasia; Hypertrophy; Male; Methimazole; Neoplasms; Rats; Thyroid Diseases; Thyroid Gland; Thyroid Neoplasms

Topics: Animals; Female; Freund's Adjuvant; Guinea Pigs; Hyperplasia; Immunization; Male; Methimazole; Microscopy, Electron; Thyroid Hormones; Thyroiditis; Thyrotropin; Triiodothyronine