Increased Serum Thyroid-stimulating Hormone Research Articles

Subclinical Hypothyroidism: A Misnomer in Search of a New Name

361 SUBCLINICAL HYPOTHYROIDISM (SH), a rather frequent disorder characterized by increased serum thyrotropin (TSH) levels and normal serum concentrations of free thyroxine (FT4) and free triiodothyronine (FT3), has been initially introduced as “preclinical hypothyroidism” in the early 1970s (1). The term SH was presented in the middle 1970s, shortly after the introduction of the first TSH radioimmunoassays, indicating a clinical asymptomatic condition accompanied by a laboratory finding (2). The prevalence of SH is genderand age-dependent and its coexistence with thyroid antibodies increases about 5% a year the risk of progression to overt hypothyroidism (3,4). For more than two decades an animosity existed regarding the clinical significance and the necessity to treat or not to treat this condition (5,6). Recently, the apparent innocuous condition has been proved to be associated with significant metabolic changes and potential consequences. A series of studies has demonstrated that the so-called “SH” might be linked to lipid disorders, vascular, hematologic, and neuropsychiatric disturbances (7,10). An impaired ventricular function as well as cardiovascular and respiratory maladaptation to exercise have also been described (11). Additionally, the presence of SH in pregnancy has been postulated to be associated with perceptible reduction in IQ of the offspring (12). Sunami is a post-earthquake wave in the Pacific that may grow slowly but strikes fiercely, provoking marked damages. SH may also slowly evolve and induce consistent damages, functioning as an independent risk factor for atherosclerosis and myocardial infarction in postmenopausal women as has been recently found in the Rotterdam study (13). In the same study, it has been postulated that atherosclerosis is involved in the mechanism by which SH and myocardial infarction are associated, and it has also been calculated that subclinical hypothyroidism may contribute to 14% of all cases of myocardial infarction (13). Thus, the SH is enriched with a wide spectrum of findings, which are usually present in overt hypothyroidism. The consistent presence and intensity of these symptoms might be dependent on the degree of thyroid insufficiency. Currently, the introduction of third-generation TSH assays enables us to reconsider the border of euthyroid TSH levels. Indeed, evidence increasingly indicates that metabolic alterations and vascular abnormalities such as endothelial-dependent vasodilatation are already present in patients with TSH levels above 2 mU/L and that the severity of these changes is highly correlated with TSH levels (8,14). Furthermore, the Whickham study clearly showed that increased risk of developing hypothyroidism was associated with TSH levels as low as 2 mU/L (3). Consequently, these findings reveal that SH is a gradual phenomenon and may extend the borders of confinement of SH to a considerably lower level. Therefore, one could propose an adjustment of the classification of hypothyroidism proposed by Staub et al. (15), i.e., in grade I (TSH , 6 mU/L), grade II (TSH 6 to 12 mU/L), and grade III (TSH. 12 mU/L). A suggestion could be to emphasize the clinical findings and subdivide hypothyroidism into minimal, mild, and overt hypothyroidism and hence, correlate to serum TSH concentrations (Table 1). A similar stratification introducing an evidence-based lower cutoff point to identify SH may expose the innate danger of the disease for metabolic and vascular alterations. It could

Investigating the paradox of hypothyroidism and increased serum thyrotropin (TSH) levels in Sheehan's syndrome: characterization of TSH carbohydrate content and bioactivity.

Serum TSH levels are often paradoxically elevated in patients with hypothyroidism due to Sheehan's syndrome. To investigate this apparent discrepancy, the biological activity and glycosylation of serum TSH were studied in 9 untreated patients with Sheehan's syndrome and 11 normal controls. TSH bioassay was based on cAMP generation, measured by RIA, in a culture system of CHO cells transfected with recombinant human TSH receptor. The oligosaccharide branching of TSH was studied by Con A lectin affinity chromatography, which discriminates TSH isoforms according to their mannose content, and the sialic acid content of TSH was studied by Ricinus communis affinity chromatography in combination with enzymatic removal of sialic acid with neuraminidase treatment. TSH bioactivity was expressed as the ratio between biological and immunofluorometric assays (B/I). Bioactive TSH concentrations were calculated by multiplying serum TSH intrinsic bioactivity by serum immunoreactive TSH concentration (B/I x I). Serum free T(4) (FT(4)) levels were lower in patients than in controls (3.7 +/- 0.4 vs. 14.0 +/- 0.9 pmol/L, respectively; P < 0.0001). Circulating immunoreactive TSH was higher in patients with Sheehan's syndrome than in controls (3.8 +/- 0.8 vs. 1.8 +/- 0.2 mU/L, respectively; P = 0.01). In contrast, TSH B/I was significantly decreased in Sheehan's patients compared with controls (0.6 +/- 0.4 vs. 1.7 +/- 0.8, respectively; P = 0.003). However, the resultant bioactive TSH concentrations in serum of Sheehan's patients were not significantly different from control values (2.1 +/- 0.6 vs. 3.0 +/- 0.4; P = 0.25). A significant correlation was found between the bioactive TSH concentrations and serum FT(4) levels in patients with Sheehan's syndrome (r = 0.66; P = 0.05), but not between serum immunoreactive TSH and FT(4) levels (r = 0.21; P = 0.59) or between intrinsic TSH bioactivity and FT(4) levels (r = 0.56; P = 0.12). The Con A chromatography of serum TSH showed a similar distribution (0.3 < P < 0.5) of unbound, weakly bound, and firmly bound TSH in Sheehan's patients (16%, 38%, and 47%, respectively) and controls (15%, 34%, and 52%, respectively). The ricin chromatography of serum TSH showed a higher proportion of sialylated TSH molecules in Sheehan's patients than in controls (55% vs. 29%; P = 0.02). These results show that circulating TSH in Sheehan's syndrome, albeit increased, has decreased biological activity. The relevance of this finding is supported by the direct correlation between bioactive serum TSH concentrations and circulating FT(4). The reduced intrinsic TSH bioactivity in pituitary hypothyroidism of Sheehan's syndrome results from increased sialylation of TSH.

Differential effects of microsomal enzyme inducers on in vitro thyroxine (T(4)) and triiodothyronine (T(3)) glucuronidation.

Microsomal enzyme inducers that increase UDP-glucuronosyltransferase (UDP-GT) activity are suspected to affect the thyroid gland by increasing the glucuronidation of T(4), which reduces serum thyroxine (T(4)). In response to reduced serum T(4), serum thyroid-stimulating hormone (TSH) increases. However, not all microsomal enzyme inducers that reduce serum T(4) produce an increase in serum TSH. We have shown that serum TSH is increased the most in rats treated with the microsomal enzyme inducers phenobarbital (PB) or pregnenolone-16alpha-carbonitrile (PCN), whereas TSH is affected less in rats treated with 3-methylcholanthrene (3MC) and Aroclor 1254 (PCB). It is unclear why serum TSH is differentially affected by various microsomal enzyme inducers. We propose that the glucuronidation of T(3) might be the reason serum TSH is increased by some microsomal enzyme inducers but not by others. Male Sprague-Dawley rats were fed either a basal diet or a diet containing PB (at 300, 600, 1200, or 2400 ppm), PCN (at 200, 400, 800, or 1600 ppm), 3MC (at 50, 100, 200, or 400 ppm), or PCB (at 25, 50, 100, or 200 ppm) for 7 days; and T(4) and T(3) UDP-GT activities were then determined. T(4) UDP-GT activity was increased in rats treated with PB (120%), PCN (250 to 400%), 3MC (400 to 600%), or PCB (300 to 430%). In contrast, T(3) UDP-GT activity was increased in rats treated with PB (90%) or PCN (120 to 200%), whereas 3MC and PCB treatments did not have an appreciable effect. In conclusion, differential effects on T(3) glucuronosyltransferase activity were found in rats treated with microsomal enzyme inducers.

Latent Autoimmune Thyroiditis in Untreated Patients with HCV Chronic Hepatitis: a Case-control Study

In order to establish a relationship between Hepatitis C virus (HCV) chronic infection and autoimmune thyroiditis, 97 untreated patients with biopsy-proven HCV chronic hepatitis and 97 controls were studied. An ultrasound examination of the thyroid and an assay of serum thyroid-stimulating hormone (TSH), thyroid hormones and anti-thyroid antibodies were performed in all cases. The overall prevalence of thyroid abnormalities was higher in patients than in controls (17 vs. 4%,P <0.01) and the prevalence of anti-thyroid antibodies was significantly different between the two groups (P<0.02). HCV patients with (n=13) compared to HCV patients without anti-thyroid antibodies (n=84) were older, predominantly female, and more frequently had increased serum TSH levels or a hypoechogenic pattern of the thyroid gland, while Knodell's score and prevalence of cirrhosis were similar. Latent autoimmune thyroiditis is more frequent in untreated HCV patients than in controls. This finding raises questions about the mechanism of autoimmunity induced by HCV and provides an explanation for the high rate of overt autoimmune thyroiditis during interferon treatment in these patients.

Effects of Microsomal Enzyme Inducers on Thyroid-Follicular Cell Proliferation, Hyperplasia, and Hypertrophy

The microsomal enzyme inducer (MEI), phenobarbital (PB), has been proposed to promote thyroid tumors by increasing the biotransformation and elimination of T4, resulting in an increase in serum thyroid-stimulating hormone (TSH). In turn, TSH stimulates thyroid gland function, growth, and ultimately neoplasia. The dose-dependent effects of MEI on thyroid-follicular cell proliferation, a measure of thyroid gland growth, has not been reported. In the present study, it was hypothesized that MEIs that increase TSH would stimulate thyroid-follicular cell proliferation and the total number of thyroid-follicular cells. Male Sprague–Dawley rats were fed either a basal diet or a diet containing PB (at 300, 600, 1200, or 2400 ppm), pregnenolone-16α-carbonitrile (PCN) (at 200, 400, 800, or 1600 ppm), 3-methylcholanthrene (3MC) (at 50, 100, 200, or 400 ppm), or Aroclor 1254 (PCB) (at 25, 50, 100, or 200 ppm) for 7 days. PB and PCN increased TSH 65% and 95%, respectively, whereas 3MC and PCB did not appreciably affect TSH. PB and PCN increased thyroid-follicular cell proliferation 625% and 1200%, respectively, whereas 3MC and PCB did not have a consistent or appreciable effect. The total number of thyroid-follicular cells was not significantly increased by MEI treatment. In conclusion, small increases in TSH by PB and PCN produced large increases in thyroid-follicular cell proliferation, which did not result in a comparable increase in the total number of thyroid-follicular cells. Furthermore, MEI that did not increase TSH did not consistently or appreciably increase thyroid-follicular cell proliferation or cell number.

Altered thyroid status modulates portal pressure in normal rats.

Disturbances in thyroid function in humans and experimental animal models have been associated with alterations in liver function and portal circulation. We have previously shown that hypothyroidism can significantly reduce portal pressure in portal vein ligated rats as well as inhibit the development of cirrhosis and fulminant hepatic failure following toxic liver injury. The aim of this study was to determine the effects of increased and decreased thyroid function on portal pressure in rats with normal liver histology and portal circulation. Three groups of 12 Wistar rats each were studied over a 30 day period: euthyroid (Group 1), hyperthyroid (Group 2) and hypothyroid (Group 3). Hyperthyroidism was induced by subcutaneous injection of triiodothyronine (400 microg/100g body weight) every ten days during the study period. Hypothyroidism was induced by methimazole (0.04% in drinking water) from 2 weeks prior to and throughout the 30 day study. Serum triiodothyronine (T3) and thyroid stimulating hormone (TSH) levels were determined to confirm the induction of hyper- and hypothyroidism. Portal pressure was assessed by direct catheterization of the portal vein prior to sacrifice. Indirect confirmation of changes in portal circulation was obtained by determining splenic weight at the time of sacrificing the animals. Animals were sacrificed at 10 day intervals throughout the 30 day study. Triiodothyronine treated rats were hyperthyroid compared to controls, with an elevation in serum T3 levels (3.8+/-0.9 mmol/L vs 1.3+/-0.4 mmol/L, p<0.05). In rats treated with methimazole, hypothyroidism was confirmed by a 7-fold increase in serum TSH compared to controls (1.8+/-0.4 vs 0.24+/-0.04 mmol/L, p<0.01). Portal pressure was significantly higher in the triiodothyronine treated rats compared to controls (12.8+/-1.7 and 9.6+/-0.75 cm H2O, p<0.001). Splenic weights in hyperthyroid rats were significantly higher than in controls (579+/-44 vs 478+/-46 mg, p<0.01). Portal pressure was significantly lower in the methimazole treated group compared to the control group (8.13+/-0.68 vs 9.6+/-0.75 cm H2O, p<0.01) as were splenic weights (400+/-33 vs 478+/-46 mg, p<0.01). These studies demonstrate that disturbed thyroid function exerts significant hemodynamic effects on the portal circulation in normal rats and complements results from previous similar studies in cirrhotic animals.

Detection of thyroid toxicants in a tier I screening battery and alterations in thyroid endpoints over 28 days of exposure.

Phenobarbital (PB), a thyroid hormone excretion enhancer, and propylthiouracil (PTU), a thyroid hormone-synthesis inhibitor, have been examined in a Tier I screening battery for detecting endocrine-active compounds (EACs). The Tier I battery incorporates two short-term in vivo tests (5-day ovariectomized female battery and 15-day intact male battery using Sprague-Dawley rats) and an in vitro yeast transactivation system (YTS). In addition to the Tier I battery, thyroid endpoints (serum hormone concentrations, liver and thyroid weights, thyroid histology, and UDP-glucuronyltransferase [UDP-GT] and 5'-deiodinase activities) have been evaluated in a 15-day dietary restriction experiment. The purpose was to assess possible confounding of results due to treatment-related decreases in body weight. Finally, several thyroid-related endpoints (serum hormone concentrations, hepatic UDP-GT activity, thyroid weights, thyroid follicular cell proliferation, and histopathology of the thyroid gland) have been evaluated for their utility in detecting thyroid-modulating effects after 1, 2, or 4 weeks of treatment with PB or PTU. In the female battery, changes in thyroid endpoints following PB administration, were limited to decreased serum tri-iodothyronine (T3) and thyroxine (T4) concentrations. There were no changes in thyroid stimulating hormone (TSH) concentrations or in thyroid gland histology. In the male battery, PB administration increased serum TSH and decreased T3 and T4 concentrations. The most sensitive indicator of PB-induced thyroid effects in the male battery was thyroid histology (pale staining and/or depleted colloid). In the female battery, PTU administration produced increases in TSH concentrations, decreases in T3 and T4 concentrations, and microscopic changes (hypertrophy/hyperplasia, colloid depletion) in the thyroid gland. In the male battery, PTU administration caused thyroid gland hypertrophy/hyperplasia and colloid depletion, and the expected thyroid hormonal alterations (increased TSH, and decreased serum T3 and T4 concentrations). The dietary restriction study demonstrated that possible confounding of the data can occur with the thyroid endpoints when body weight decrements are 15% or greater. In the thyroid time course experiment, PB produced increased UDP-GT activity (at all time points), increased serum TSH (4-week time point), decreased serum T3 (1-and 2-week time points) and T4 (all time points), increased relative thyroid weight (2- and 4-week time points), and increased thyroid follicular cell proliferation (1- and 2-week time points). Histological effects in PB-treated rats were limited to mild colloid depletion at the 2- and 4-week time points. At all three time points, PTU increased relative thyroid weight, increased serum TSH, decreased serum T3 and T4, increased thyroid follicular cell proliferation, and produced thyroid gland hyperplasia/hypertrophy. Thyroid gland histopathology, coupled with decreased serum T4 concentrations, has been proposed as the most useful criteria for identifying thyroid toxicants. These data suggest that thyroid gland weight, coupled with thyroid hormone analyses and thyroid histology, are the most reliable endpoints for identifying thyroid gland toxicants in a short-duration screening battery. The data further suggest that 2 weeks is the optimal time point for identifying thyroid toxicants based on the 9 endpoints examined. Hence, the 2-week male battery currently being validated as part of this report should be an effective screen for detecting both potent and weak thyroid toxicants.

Dose-response examination of UDP-glucuronosyltransferase inducers and their ability to increase both TGF-beta expression and thyroid follicular cell apoptosis.

Exposure to certain microsomal enzyme inducers that increase UDP-glucuronosyltransferase (UDP-GT) activity decreases thyroid hormone levels, which may lead to a subsequent increase in thyroid-stimulating hormone (TSH). This elevation of serum TSH has many effects on the thyroid, including increasing thyroid follicular cell proliferation, leading to hyperplasia. While induction of UDP-GT activity decreases thyroid hormone levels by enhancing biotransformation and subsequent biliary secretion, only certain UDP-GT inducers exhibit the ability to increase serum TSH levels. For example, phenobarbital (PB) and pregnenolone-16alpha-carbonitrile (PCN) increase serum levels of TSH, while 3-methylcholanthrene (3MC) and Aroclor 1254 (PCB) do not. Increased serum TSH concentration also enhances thyroid gland expression of TGF-beta1, an anti-proliferative, pro-apoptotic protein. In a previous study in our laboratory, rats were treated for various times (up to 90 days) with PB and PCN, which increased TGF-beta1 protein and apoptosis. The present study was designed to examine the dose-response effect of TSH-increasing (PB and PCN) and nonincreasing (3MC and PCB) UDP-GT inducers on apoptosis and TGF-beta1. PB and PCN, UDP-GT inducing compounds which increase serum TSH, increased the percentage of TGF-beta1-positive follicular cells and increased apoptosis. In contrast, UDP-GT inducers that did not increase TSH (3MC and PCB) did not alter cell death or TGF-beta production. These data suggest that the increase of TGF-beta by TSH may serve to regulate the growth of hyperplastic thyroid.

Mechanism for inhibition of thyroid peroxidase by leucomalachite green.

The triphenylmethane dye, malachite green (MG), is used to treat and prevent fungal and parasitic infections in the aquaculture industry. It has been reported that the reduced metabolite of MG, leucomalachite green (LMG), accumulates in the tissues of fish treated with MG. MG is structurally related to other triphenylmethane dyes (e.g., gentian violet and pararosaniline) that are carcinogenic in the liver, thyroid, and other organs of experimental animals. The ability of LMG to inhibit thyroid peroxidase (TPO), the enzyme that catalyzes the iodination and coupling reactions required for thyroid hormone synthesis, was determined in this study. LMG inhibited TPO-catalyzed tyrosine iodination (half-maximal inhibition at ca. 10 microM). LMG also inhibited the TPO-catalyzed formation of thyroxine in low-iodine human goiter thyroglobulin (half-maximal inhibition at ca. 10 microM) using a model system that measures simultaneous iodination and coupling. Direct inhibition of the coupling reaction by LMG was shown using a coupling-only system containing chemically preiodinated thyroglobulin as the substrate. Incubation of LMG with TPO, iodide, and tyrosine in the presence of a H2O2-generating system yielded oxidation products that were identified by using on-line LC/APCI-MS as desmethyl LMG, 2desmethyl LMG, 3desmethyl LMG, MG, and MG N-oxide. Similar products from LMG were observed in incubations with TPO and H2O2 alone. These findings suggest that the anti-thyroid effects (increased serum thyroid-stimulating hormone and decreased serum thyroxine) observed in rats treated with LMG result from blockade of hormone synthesis through alternate substrate inhibition and that chronic exposure could cause thyroid follicular cell tumors through a hormonal mechanism. The observed TPO-catalyzed oxidative demethylation of LMG to a primary arylamine also suggests a genotoxic mechanism for tumor formation is possible.

Thyroid abnormalities after therapeutic external radiation

The thyroid gland is the largest pure endocrine gland in the body and one of the organs most likely to produce clinically significant abnormalities after therapeutic external radiation. Radiation doses to the thyroid that exceed approximately 26 Gy frequently produce hypothyroidism, which may be clinically overt or subclinical, as manifested by increased serum thyrotropin and normal serum-free thyroxine concentrations. Pituitary or hypothalamic hypothyroidism may arise when the pituitary region receives doses exceeding 50 Gy with conventional, 1.8–2 Gy fractionation. Direct irradiation of the thyroid may increase the risk of Graves' disease or euthyroid Graves' ophthalmopathy. Silent thyroiditis, cystic degeneration, benign adenoma, and thyroid cancer have been observed after therapeutically relevant doses of external radiation. Direct or incidental thyroid irradiation increases the risk for well-differentiated, papillary, and follicular thyroid cancer from 15- to 53-fold. Thyroid cancer risk is highest following radiation at a young age, decreases with increasing age at treatment, and increases with follow-up duration. The potentially prolonged latent period between radiation exposure and the development of thyroid dysfunction, thyroid nodularity, and thyroid cancer means that individuals who have received neck or pituitary irradiation require careful, periodic clinical and laboratory evaluation to avoid excess morbidity.

STRUCTURE-ACTIVITY RELATIONSHIPS IN 5-SUBSTITUTED 3-AMINO-1,2,4-TRIAZOLES-INDUCED GOITERS IN RATS

The goitrogenic actions of 5-substituted 3-amino-l, 2, 4-triazoles, 3-amino-5-mercapto-l, 2, 4-triazole (AMTZ), 3-amino-1, 2, 4-triazole-5-carboxylic acid (ATZC), 3, 5-diamino-l, 2, 4-triazole (DTZ), 3-amino-5-methylthio-l, 2, 4-triazole (AMTTZ), and 3-amino-1, 2, 4- triazole (ATZ) were compared in rats. ATZ, AMTZ, ATZC, and DTZ inhibited the thyroid peroxidase (TPO)-catalyzed oxidation of guaiacol in vitro, exhibiting the order of antithyroid activity ATZ>AMTZ>ATZC>DTZ. In in vivo experiments, ATZ, ATZC, or AMTZ inhibited TPO activity, and induced goiter accompanied by decrease in serum thyroid hormone and increase in serum thyroid-stimulating hormone in rats. These antithyroid activities were shown in order of ATZ>ATZC>AMTZ. The TPO inhibitory action of ATZC in vivo was weaker than that of AMTZ, but it was more persistent than AMTZ. The anti-TPO action of DTZ disappeared in vivo, and AMTTZ showed no effects in vitro and in vivo. These results show that ATZC, AMTZ, and DTZ potentially have the anti-TPO activity like as ATZ and the 5-position site of ATZ would have a very important meaning to determine the antithyroid action of ATZ. In addition, the results strongly suggest that the anti-thyroid action depends on the substitute but not on the parental compound.

Propylthiouracil in psoriasis: Results of an open trial

Propylthiouracil (PTU) is an antithyroid thioureylene that has immune modulatory and free radical scavenging abilities. In view of the immunomodulatory effects of PTU, we decided to study the therapeutic response of patients with psoriasis to oral PTU. Our purpose was to study the effect of oral PTU in patients with stable plaque psoriasis. Oral PTU, 100 mg, was administered every 8 hours for 8 weeks to 10 patients with long-standing psoriasis. Skin biopsy specimens were taken from the lesions before and at the end of the study. Clinical response was monitored with the Psoriasis Area and Severity Index scoring system. Histologic scores were graded with a 5-point grading scale. Complete blood cell count was obtained at the beginning and at the end of the study. Thyroid-stimulating hormone (TSH) was obtained at the beginning and every 2 weeks thereafter until completion of the study. Three patients dropped out of the study. Of the remaining seven, two showed near-complete resolution of their psoriatic lesions, whereas the remainder showed moderate improvement in their clinical scores. Histologic scores were significantly improved in the group with all but one patient showing improvement or no change. Thyroid function tests were unchanged in all but one patient who showed a slight increase in serum TSH at the sixth week of therapy. Because of its low toxicity relative to other oral treatments of psoriasis, PTU may have a role in the treatment of patients with this disorder.

Hormonal disregulation mechanism in the rat thyroid tumor induced by diniconazole.

To assess the toxicological significance of thyroidal tumor observed slightly in a long-term rat study with diniconazole, (E)-1-(2,4-dichlorophenyl)- 4,4-dimethyl-2-(1,2,4-triazol-1-yl)-1-penten-3-ol, a 3-month subacute feeding study was conducted in male Crj: CD (SD) rats by administering diniconazole in diet at concentrations of 0, 100, 1,000, or 2,000 ppm. Examinations mainly for thyroid functions were performed at Weeks 2, 4 and 13. Measurement of serum hormone levels revealed continuous decreases in serum thyroxine (T4) and free T4 levels at and above 1,000 ppm and increase in serum thyroid stimulating hormone (TSH) level at 2,000 ppm concurrently with liver weight and hepatic UDP-glucuronyltransferase (UDP-GT) increases at and above 1,000 ppm. No changes were observed in serum triiodothyronine (T3) and free T3 levels. Increase in thyroid uptake of 125I and organification of 125I in the thyroid at 2,000 ppm and thyroid follicular cell hyperplasia at and above 1,000 ppm were also observed. However, no compound-related changes were observed in autopsy and organ weight in the thyroid. Based on the above results, diniconazole induces increases in the hepatic UDP-GT activity and the thyroid hormone excretion from the liver. The increased excretion of thyroid hormones causes decrease in serum T4 and free T4 levels, triggering the feedback mechanism of the pituitary gland, promotion of TSH release from the pituitary gland and increase in serum TSH level. The increased serum TSH level probably leads to increased 125I uptake of thyroid and thyroid follicular cell hyperplasia. Thus, the thyroid tumorigenesis in rats treated with diniconazole is due to the secondary overstimulant effect on the thyroid by increased serum TSH level. The toxicological significance in humans is extremely low and it is unlikely that diniconazole would increase thyroid tumor in humans even if diniconazole were to alter normal thyroid hormone level in humans.

The effect of hypothyroidism on Sertoli cell proliferation and differentiation and hormone levels during testicular development in the rat.

In this study we show that 6-propyl-2-thiouracil (PTU) treatment of Wistar rats from birth up to day 26 p.p. retards the morphological differentiation of Sertoli cells, and prolongs the proliferation of these cells up to day 30. Sertoli cell numbers per testis, determined at day 36, were increased by 84% compared to controls. PTU treatment increased serum thyroid-stimulating hormone (TSH) levels and reduced serum levels of thyroxine (T4) from 5 days onwards, indicative of severe hypothyroidism. Follicle-stimulating hormone (FSH) levels were reduced from day 5 to 9, normal at day 12 and 16, and reduced again from day 20 to 36. Inhibin levels were decreased from day 9 to 20 and increased at 36 days of age. The increase in the number of Sertoli cells per testis in PTU treated rats, as has been reported in the present study, is likely to be responsible for the increased testis size observed by other groups (1) in these animals, when adult.

The effect of hypothyroidism on Sertoli cell proliferation and differentiation and hormone levels during testicular development in the rat

In this study we show that 6-propyl-2-thiouracil (PTU) treatment of Wistar rats from birth up to day 26 p.p. retards the morphological differentiation of Sertoli cells, and prolongs the proliferation of these cells up to day 30. Sertoli cell numbers per testis, determined at day 36, were increased by 84% compared to controls. PTU treatment increased serum thyroid-stimulating hormone (TSH) levels and reduced serum levels of thyroxine (T4) from 5 days onwards, indicative of severe hypothyroidism. Follicle-stimulating hormone (FSH) levels were reduced from day 5 to 9, normal at day 12 and 16, and reduced again from day 20 to 36. Inhibin levels were decreased from day 9 to 20 and increased at 36 days of age. The increase in the number of Sertoli cells per testis in PTU treated rats, as has been reported in the present study, is likely to be responsible for the increased testis size observed by other groups (1) in these animals, when adult.

Hormonal control of manganese transport in the mouse thyroid.

The present study deals with a possible mechanism controlling the transport of manganese (Mn), an essential trace element, from the circulation to the thyroid. Mice were pretreated with propylthiouracil (PTU) or triiodothyronine (T3), and a measurement of the thyroid:serum concentration ratio (T/S) of radioactive manganese (54Mn) was carried out. The T/S of 54Mn was greatly enhanced by PTU, but reduced by T3. Several methods were used to demonstrate that the T/S of 54Mn depends upon the level of thyroid-stimulating hormone (TSH) in the serum. First, bovine TSH was injected into mice; an increase in the T/S resulted. Secondly, serum thyroxine and T3 levels measured by radioimmunoassay (RIA) suggested that PTU produced an increase in serum TSH and T3 a decrease. However, direct measurement of mouse TSH by RIA for rat TSH failed to produce proof of any changes in TSH level, owing to poor cross-reactivity. Taking all the information into account, it is concluded that Mn-transport into the thyroid is controlled by the thyroid state.

Studies on the Mechanism of Simvastatin-Induced Thyroid Hypertrophy and Follicular Cell Adenoma in the Rat

Female Sprague-Dawley rats were treated with either simvastatin (a novel competitive inhibitor of HMG CoA reductase) or phenobarbital (positive control) to ascertain the possible relationship between the effects of simvastatin on hepatic metabolism and the thyroid hypertrophy and follicular cell adenomas which it produces in this strain of rat. The test compounds were administered orally at doses of 100 mg/kg (divided doses at 50 mg/kg, b.i.d.). (This dose of simvastatin represents approximately 250 times the human dose.) After 5 weeks of treatment, either simvastatin or phenobarbital produced significant increases (35% and 39% above control, respectively) in serum thyroid stimulating hormone (TSH), a significant increase (39% and 120% above control, respectively) in the systemic clearance of 125I-thyroxine, and slight decreases in serum thyroxine levels. Statistically significant increases in liver and thyroid weights were associated with phenobarbital treatment. With simvastatin, increased liver weights occurred. At the microscopic level, thyroid hypertrophy was observed in all phenobarbital-treated rats and to a lesser degree in most simvastatin-treated animals. Simvastatin did not markedly alter liver microsomal enzyme activities with the exception of the anticipated induction of HMG CoA reductase (which increased approximately 4.4-fold). Conversely, phenobarbital produced large increases in liver microsomal enzymes, including glucuronosyl transferase, but did not affect the activity of HMG CoA reductase. Therefore, the increased clearance of thyroxine in simvastatin-treated female rats was not associated with enzyme induction but may have been related to the increase in functional liver mass produced by this compound at this dose.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of pre-operative potassium iodide therapy on antibody production

Previous studies have suggested that iodide may increase the incidence of thyroid disease and anti-thyroid antibodies in predisposed individuals. This study has considered the effects of pre-operative potassium iodide (60 mg twice daily, for 10 days) on the immune system of patients with Graves' disease. The treatment regimen used maintained all patients in a clinically and biochemically euthyroid state prior to surgery. Potassium iodide significantly increased serum thyrotropin receptor antibody levels and B cell activity as determined by increased immunoglobulin production from mitogen stimulated peripheral blood lymphocytes. These effects were not observed in the two control groups of Graves' disease patients. Our in vivo findings would support previous in vitro work showing that potassium iodide does act on the immune system and this may be the mechanism by which iodide induces thyroid dysfunction in predisposed individuals.

Endocrine Effects of Blinding in Male Syrian Hamsters Are Associated With Increased Hypothalamic 5‐Hydroxyindoleacetic Acid/Serotonin Ratios

The antigonadal, antithyroid, and antiadrenal effects of blinding were studied in male Syrian hamsters receiving propylthiouracil (PTU) or PTU plus thyroxine (T4) replacement. Ten weeks after blinding, the expected gonadal involution and reduction of circulating levels of T4, as well as a reduction of circulating levels of corticosterone, were observed. T4 treatment significantly increased testicular weights, but it did not prevent gonadal involution. Neither PTU nor T4 administration significantly influenced the inhibition of serum corticosterone levels observed in blinded hamsters. The increase in serum thyroid-stimulating hormone (TSH) observed in hypothyroid (PTU-treated) hamsters was significantly greater in intact hamsters than in blind hamsters. Blinding was associated with a small but highly significant increase in ratios of 5-hydroxyindoleacetic acid (5HIAA) to serotonin (5HT) in extracts of the medial basal hypothalamus. Based on the assumption that 5HIAA represents primarily intraneuronal metabolism of excess 5HT, the present results are consistent with reduced 5HT release in blinded hamsters. Daily evening melatonin administration also increased the 5HIAA/5HT ratios of the mediobasal hypothalamus concurrently with gonadal involution, reduction of circulating levels of T4, and reduction of circulating levels of corticosterone. These results are consistent with the view that serotonergic neurons entering the hypothalamus are components of the photoneuroendocrine system of the hamster.

Involvement of D1 dopamine receptors in the nicotine-induced neuro-endocrine effects and depletion of diencephalic catecholamine stores in the male rat.

Male rats were treated acutely with nicotine (4 x 2 mg/kg, 30-min time intervals, total treatment time 2 h) or exposed to cigarette smoke from 4 x 1 cigarette (30-min time intervals, total treatment time 2 h). Some rats were pretreated with the D1 dopamine (DA) receptor antagonist SCH 23390 (0.1-3.0 mg/kg, i.p.), or with the D2 DA receptor antagonists remoxipride and raclopride (1 mg/kg, i.p.), or with the 5-hydroxytryptamine 2 (5-HT2) receptor antagonist ketanserin (0.3 mg/kg, i.p.) 5 min before nicotine treatment or the acute intermittent exposure to cigarette smoke. Some rats were treated with the D1 DA receptor agonist SK&F 38393 (1-10 mg/kg, i.p.) 15 min, 30 min or 2 h before decapitation. Hypothalamic and pre-optic catecholamine (CA) levels were measured by quantitative histofluorimetry in discrete DA and noradrenaline (NA) nerve terminal systems. Serum thyroid-stimulating hormone (TSH), prolactin, luteinizing hormone (LH), follicle-stimulating hormone (FSH), vasopressin, corticosterone and testosterone levels were determined by radioimmunoassay procedures. Nicotine treatment and to a minor degree also acute intermittent exposure to cigarette smoke produced a reduction in serum prolactin, LH and TSH but not in serum FSH, vasopressin and testosterone levels. Nicotine treatment also increased serum corticosterone levels. Pretreatment with the D1 DA receptor antagonist SCH 23390 (1-3 mg/kg) counteracted the lowering of serum LH, but not of prolactin and TSH levels induced by nicotine or exposure to cigarette smoke. SCH 23390 alone (1-3 mg/kg) increased serum TSH levels. Remoxipride, raclopride or ketanserin did not counteract any of the neuro-endocrine actions induced by nicotine treatment. However, ketanserin alone lowered serum prolactin levels. SK&F 38393 increased serum TSH, prolactin and LH levels. It was found that nicotine treatment and exposure to cigarette smoke with few exceptions produced a depletion of CA stores in NA and DA nerve terminals of the hypothalamus, pre-optic area and median eminence which was counteracted by SCH 23390 (1 mg/kg) but not by remoxipride, raclopride (1 mg/kg) or ketanserin (0.3 mg/kg). The results indicate that D1 but not D2 DA or 5-HT2 receptors may modulate the NA and DA release in the median eminence, the hypothalamus and the pre-optic area induced by nicotinic cholinoceptor activation. Furthermore, D1 DA receptors in the median eminence may at least in part mediate the inhibitory effects of nicotine on LH but not on TSH and prolactin secretion, although there appears to exist a D1 DA receptor in the median eminence which inhibits TSH secretion.(ABSTRACT TRUNCATED AT 400 WORDS)