Showing papers on "Propylthiouracil published in 1977"

Modulation of Pituitary Thyrotropin Releasing Hormone Receptor Levels by Estrogens and Thyroid Hormones

Abstract: The effect of estradiol and thyroid hormone treatment on pituitary TRH binding and TSH and PRL responses to the neurohormone was studied. A significant increase in the number of pituitary TRH binding sites was observed between 2 and 4 days after daily administration of estradiol benzoate with a plateau at 300% of control being reached at 7 days. Plasma PRL levels showed a similar early pattern of response. In animals rendered hypothyroid by a 2-month treatment with propylthiouracil or 1 month after surgical thyroidectomy, the level of pituitary TRH receptors was increased approximately 2-fold, this elevation being completely reversed by treatment with thyroid hormone. Estradiol-17beta administered with L-thyroxine partially reversed the inhibitory effect of thyroid hormone on TRH receptor levels in hypothyroid animals. The antagonism between estrogens and thyroid hormone is also apparent on the TSH response to TRH since estrogen administration can reverse the marked inhibition by thyroxine of the TSH response to TRH either partially or completely in intact and hypothyroid animals, respectively. The PRL response to TRH is 55 and 40% inhibited in hypothyroid and intact rats, respectively, by thyroid hormone when combined with estrogen treatment. The present data clearly show that estrogens and thyroid hormones can affect TSH and PRL secretion, the effect of estrogens being predominantly on PRL secretion while thyroid hormone affects mainly TSH. The close correlation observed between the level of TRH receptors and PRL and TSH responses to TRH suggests that estrogens and, to a lesser extent, thyroid hormones, exert their action by modulation of the level of receptors for the neurohormone in both thyrotrophs and mammotrophs.

The placental transfer of propylthiouracil, methimazole and carbimazole.

Abstract: The placental transfer of 35S-labelled methimazole (MMI), carbimazole and propylthiouracil (PTU) has been examined in the rat in late pregnancy and in patients undergoing therapeutic abortion. Although rapid equilibrium of fetal and maternal serum radioactivity (FS:MS ratio 1:1) occurred after iv administration of 35S-carbimazole or 35S-MMI in rats, a persistent fetal to maternal ratio of less than one was observed after 35S-PTU administration. Results from human studies after a single oral dose indicate that, as in the rat, the placenta appeared to be more permeable to 35S-MMI than to 35S-PTU as shown by the marked difference in fetal serum:maternal serum ratios and amounts accumulated in the fetus. Localization of radioactivity in the human fetal thyroid was also observed after administration of 35S-labelled MMI, carbimazole or PTU.

Comparison of the biological effects of thyroxine and triiodothyronine in the rat.

Abstract: To compare the biological effects of thyroxine (T4) and triiodothyronine (T3), the results of varying the production rates of T3 and T4 independently were evaluated. In one set of experiments, the responses of hypothyroid rats to thyroid hormones were measured in terms of weight gain, hepatic mitochondrial alpha-glycerophosphate dehydrogenase (alphaGPD) and serum TSH. T4 was given with, and without, 6-n-propylthiouracil (PTU) and alphaGPD activity paralleled, and could completely be accounted for, by the effect of the quantities of the T3 produced. The direct role of T3 production in the maintenance of hepatic alphaGPD activity was supported by finding normal serum T3 and alphaGPD activities, but reduced T4, in rats on low iodine diet for 2 months. Only after 4 months of iodine deficiency was alphaGPD reduced in the presence of a normal serum T3. These results suggest that T4 per se plays minimal role in this system. In contrast, there were significant effects of T4 administration on stimulation of weight gain and suppression of TSH release in hypothyroid animals which were not due to the T3 produced by peripheral conversion. While T3 given parenterally was about tenfold more potent than T4 in acute suppression of TSH, PTU retreatment did not alter the acute decrease in TSH after T4 which lasted for at least 22 h, as opposed to less than 7 h for T3. Despite the direct effect of T4 on TSH suppression , acute reduction in T3 in normal rats resulted in an elevation of serum TSH even though serum T4 concentrations were unchanged or even increased at this time. The results indicate that the thyrotroph, unlike the hepatocyte, can respond acutely to both increases and decreases in either T3 or T4 production. The differential sensitivities of various tissues to T3 and T4 indicate that the relative potencies of these two hormones must be defined experimentally in terms of a specific biological effect.

Agranulocytosis and antithyroid drugs.

Abstract: Propylthiouracil and methimazole are used widely in the treatment of hyperthyroid disorders. The most important complication of the use of these drugs is depression of the neutrophilic granulocyte count. Granulocytopenia occurs in about 4 percent and agranulocytosis occurs in about 0.3 percent of treated patients. Although this depression of the granulocyte count is reversible after the drug is discontinued, serious infection frequently accompanies agranulocytosis and accounts for almost all deaths related to the drugs. It is important to be aware of the clinical features of granulocytopenic reactions due to antithyroid drugs.

Growth hormone, somatomedin and cartilage sulfation in failure of catch-up growth after propylthiouracil-induced hypothyroidism in the rat.

Abstract: Male Long-Evans rats 36 to 39 days of age were fed a diet containing 0.1% propylthiouracil (PTU) for 17 to 20 days followed by the resumption of normal diet. Growth rates of body weight and tail length decreased during PTU treatment and increased during recovery; yet only slight catch-up (compensatory) growth occurred in either body weight or tail length. Although serum thyroxine and triiodothyronine concentrations (radioimmunoassay) decreased significantly during PTU treatment, they returned to normal by recovery day 14. Pituitary immunoassayable growth hormone (GH) content and concentration dropped during PTU-feeding. By recovery day 14 there was significant, but incomplete, repletion of the gland. Serum GH during ether anesthesia was increased significantly during PTU treatment; it remained elevated (NS) and showed greater variability during recovery than in controls. Bioassayable serum somatomedin (Sm) activity decreased during PTU treatment in one of two experiments but returned to a normal level by ...

The Effect of Basal Hypothalamic Isolation on Pituitary-Thyroid Activity and the Response to Propylthiouracil

Abstract: Basal hypothalamic deafferentation extending from the posterior border of the optic chiasm to the mid-mammillary bodies resulted in depression of plasma TSH, thyroxine (T4), and triiodothyronine (T3) concentration to 50% of normal controls within 7 days. Administration of 0.15% propylthiouracil (PTU) in the diet from postoperative day 26 caused a pronounced drop in the plasma T3 level and a rise in plasma TSH level within two days in the control animals, but had little effect during this interval in the deafferented animals. After 12 days of PTU, plasma T3 and T4 concentrations had dropped to undetectable concentrations in the control animals but both were still detectable in the deafferented animals. After 25 days of PTU, plasma T4 and T3 levels were undetectable and plasma TSH levels were significantly elevated above normal in all animals. Thyroid hypertrophy at that time was as great in the deafferented as in the control rats, although plasma TSH concentration was 50% lower in the former. Administratio...

Iodinating activity of thyroid tissue in toxic diffuse goiter.

Abstract: Thyroid tissue obtained from 12 patients with Graves' disease and treated with thionamide drugs for 3-7 mo before subtotal thyroidectomy, from 12 patients with Graves' disease, similarly treated, and given 50 mug of triiodothyronine (T3) for 10 days before surgery, and from 12 euthyroid patients with solitary cold nodules was investigated to compare in vitro iodination of thyroglobulin in toxic diffuse goiter and in normal thyroid tissue. The supernates of the homogenates (105,000g) were subjected to sucrose density gradient centrifugation (5--28%) to separate the thyroglobulin fraction. The precipitates were treated with 1% digitonin and centrifuged to collect the supernate (particulate fraction). When thyroglobulin and particulate fractions obtained from the same patient were incubated with 125I-, iodide, glucose, and glucose oxidase, the amount of iodine bound to thyroglobulin was several times greater in toxic diffuse goiter than in normal thyroid tissue; administration of T3 did not affect iodination in toxic diffuse goiter. When the thyroglobulin fraction from each patient was incubated with a standardized quantity of peroxidase instead of the individual particulate fraction, the amount of iodine bound to thyroglobulin was the same among the three groups of patients. Finally, when bovine serum albumin was substituted for thyroglobulin from each of the patients, iodination of bovine serum albumin was several times greater with the particulate fraction obtained from toxic diffuse goiter tissue than with that obtained from normal tissue. The guaiacol-oxidizing activity oty. These results suggest that in vitro iodination of thyroglobulin is increased in toxic diffuse goiter even when patients are made euthyroid by treatment with thionamide drugs as well as when they are given additional T3 for 10 days before operation. The increase in iodination of thyroglobulin appears to be due to an increase in peroxidase activity in the particulate fraction.

Hyperthyroidism during pregnancy treated with propylthiouracil. The significance of maternal and foetal parameters.

Abstract: Hyperthyroidism during pregnancy may be dangerous to the infant. The major risks are prematurity and neonatal thyrotoxicosis. The latter may be due to placental transfer of thyroid stimulating immunoglobulins from mother to fetus. Of two siblings of a previously thyrotoxic mother the first had marked symptoms of neonatal thyrotoxicosis after a pregnancy where no antithyroid treatment was given. The second child had only minimal thyrotoxic symptoms but almost as high levels of thyroid hormones as the first. During the second pregnancy propylthiouracil was given to the mother from 26 weeks' gestation, because of increased fetal movements and fetal tachycardia. Fetal movements and fetal heart rate were considered to be most valuable indicators of thyroid function in the fetus. Intense control is necessary from the beginning of the second trimester.

1,1-Dichloroethylene hepatotoxicity: effect of altered thyroid function and evidence for the subcellular site of injury.

Abstract: Male Sprague‐Dawley rats were exposed for 4 hr to 1,1‐dichloroethylene (1,1‐DCE) by inhalation following an 18 hr fast. They were killed at 6 hr. Under these circumstances, prior thyroidectomy caused a decrease in the severity of the injury as measured by elevation of serum alanine‐α‐ketoglutarate transaminase (AKT), while thyroxine pretreatment (50 \ig per rat sc for 7 days) enhanced the hepatotoxicity of 1,1‐DCE as measured by lethality and serum AKT elevation. Chemical thyroidectomy using either propylthiouracil (30 mg/kg po for 7 days) or methimazole (15 mg/kg po for 7 days) also provided a degree of protection. Thyroidectomy, surgical or chemical, was associated with an increase in hepatic glutathione concentration, while thyroxine decreased the hepatic concentration of this nucleophile. Livers from rats exposed to 1,1‐DCE were found to have decreased in vitro oxygen uptake when supplied with succinate and ADP. This form of injury preceded the elevation in serum AKT, which occurred at 4 hr. Subcellul...

Effects of thyroid hormones on the evolution of monoamine oxidase activity in the brain and heart of the developing rat.

Abstract: The evolution of monoamine oxidase (MAO) activity towards tryptamine has been studied from birth to 20 days post-natal in the brain and heart of male rats. Hyperthyroidism was induced by thyroxine injections and hypothyroidism by PTU administration. The results are expressed per unit of fresh weight and per unit of protein weight. Cardiac MAO is higher in the hyperthyroid animals than in controls as soon as 5 days following birth; the difference between the 2 groups increases until 20 days. The deficiency in thyroid hormones, on the other hand, was followed by a slight decrease in the cardiac enzyme, this decrease reflecting the general deficit in protein synthesis. Brain MAO is not affected by hyperthyroidism, but a clear deficit follows PTU administration. This deficit is significant beginning at 10 days and the difference between the 2 groups increases up to 20 days. The effects of PTU-induced hypothyroidism can be corrected by thyroxine injections. Except for the decrease in the level of cardiac enzyme in hypothyroid animals, all the effects on MAO activity are independent of the total protein content of both organs.

Effects of Thyrotropin and Thyroid Hormones in Vivo on Thyroid Responsiveness to Thyrotropin in Vitro

Abstract: The thyroid gland of rats fed propylthiouracil is known to be unresponsive in vitro to thyrotropin; to investigate further the underlying mechanism groups of rats were variously treated with propylthiouracil and thyroid hormone or subjected to hypophysectomy. In vitro responsiveness of the thyroids was tested by measuring an increase in the concentration of c AMP when thyrotropin or prostaglandin E1 was added to the medium. Results showed that responsiveness to thyrotropin partially returned with rats fed prophylthiouracil and hypophysectomized 5, but not 2, days before death; hypophysectomy of normal rats led to increased in vitro responsiveness to thyrotropin and this was partially reversed by injections of thyrotropin for a week before death. Administration of thyroid hormone had little effect in these investigations and in vitro responsiveness to prostaglanding E1 was not consistently influenced by any of the in vivo regimens. From this experience we conclude that, at least as studied in vitro, circulating thyrotropin has a significant role in modulating responsiveness of the thyroid to thyrotropin.

Measurement of thyroid hormone in experimental thyroid tumours in rats.

Abstract: Rats treated with 131I and propylthiouracil were shown to develop thyroid tumours 7--9 months after treatment. In this group, the levels of total thyroxine and tri-iodothyronine, and free thyroxine and tri-iodothyronine in the serum were low, and that of TSH was raised. In a group of rats treated with 131I and then propylthiouracil and thyroxine, thyroid tumours were found despite normal concentrations of total and free thyroxine and tri-iodothyronine in the serum. The level of TSH in the serum was significantly raised in this group. Thyroid tumours were not found in the various control groups of rats.

Relationship of biochemical and morphological changes in rat thyroid and proton spin-relaxation of the tissue water.

Abstract: 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.

Effect of anti‐thyroid agents, methimazole and propylthiouracil, on brain noradrenaline content

Abstract: 1 Methimazole (1-methyl-2-mercaptoimidazole, MMI) and propylthiouracil (6-propyl-2-thiouracil, PTU) which are used in the therapy of hyperthyroidism were found to reduce brain noradrenaline (NA) content. Endogenous NA levels in rat brain were reduced from 1 to 6 h after intraperitoneal injection of MMI by doses in excess of 25 mg/kg and by PTU at a dose of 50 mg/kg. However, endogenous NA in the rat heart was only slightly reduced after 50 mg/kg of MMI, and was not affected by PTU (50 mg/kg). 2 Both MMI and PTU effectively inhibited the in vivo conversion of [3H]-dopamine into [3H]-noradrenaline ([3H]-NA) in the brain of rats after a single intraperitoneal injection of doses above 10 mg/kg (MMI) and 25 mg/kg (PTU). This inhibition by MMI and PTU was dose-dependent over the range of 10 mg/kg to 50 mg/kg, was highest after 2-3 h and continued for at least 6 h after their injection; The conversion rates returned to normal after 24 hours. 3 The results suggest that the reduction of brain NA by these drugs is, at least in part, due to the inhibition of brain dopamine beta-hydroxylase.

Effect of propylthiouracil on intestinal tumor formation by azoxymethane in rats.

Abstract: Treatment with propylthiouracil (PTU) resulted in a significant decrease in azoxymethane-induced intestinal tumors, total concentration of fecal bile acid as well as the fecal neutral steroids, cholesterol and coprostanol. Thus, a hypothyroid state induced by PTU treatment may affect intestinal carcinogenesis in this animal model by lowering the concentration of fecal bile acids and neutral steroids.

T3 toxicosis in children

Abstract: . Triiodothyronine (T3) toxicity has been well documented in adults, but only isolated cases have been reported in children. Two girls presented with firm goitres and overt hyperthyroidism. In each patient, total serum thyroxine (T4) values by competitive protein binding were normal, however total T3 values by radioimmunoassay were elevated. One patient had Graves' disease, the second patient had Hashimoto's disease which has been only infrequently associated with T3 toxicity in adults. Both patients responded to therapy with propylthiouracil. The mechanisms by which T3 is preferentially secreted in thyrotoxic states in man are poorly understood, but iodine deficiency and poor iodination of thyroglobulin may be important factors.

The thyroid in the spontaneously hypertensive rat: A light and electron microscopic study

Abstract: The present study was undertaken to seek ultrastructural changes in the thyroid gland of the spontaneously hypertensive rat which would contribute to the understanding of previously reported abnormalities in thyroid function. Light and electron microscopic observations and measurements of plasma T3 and systolic blood pressure were recorded from a colony of Wistar Kyoto rats (WKY) and of spontaneously hypertensive rats (SHR). The systolic blood pressure of SHR was significantly higher than that of WKY but the plasma T3 levels of the two groups did not differ significantly. After administration of propylthiouracil (PTU), serum T3 levels and systolic pressure of both groups decreased. The size of the thyroid follicles in SHR was highly variable throughout the gland, and the colloid contained unevenly dense areas and cell debris. The follicular cells contained slightly dilated rough surfaced endoplasmic reticulum (ER) and numerous pleomorphic bodies of uneven density. After treatment with PTU, the vessels between the follicles of SHR did not become as dilated as those in WKY but the fine structure of follicular cells in SHR was similar to that of WKY and was characteristic of the typical thyroid response to PTU administration. We suggest that the thyroid in SHR does not respond adequately to the elevated TSH levels reported to be present in these animals, although it can respond to the highly elevated TSH levels which occur with PTU administration. This impairment most probably involves defects in synthesis and/or secretion of thyroid hormones in response to TSH stimulation.