Activity In Hypothyroidism Research Articles

MECHANISTIC ROLE OF VARUNA (CRATAEVA NURVALA) EXTRACT ON THYROID GLAND AND ITS HISTOLOGY THROUGH IODOTHYRONINE DEIODINASES

Objective: Crataeva nurvala (CN) is used for its therapeutic effects, but its effect on the thyroid gland in euthyroid conditions and mechanism behind its thyrotropic activity in hypothyroidism is still not explored. This study screened the pharmacological effect of the ethanolic extract of the bark of CN on thyroid hormones, free and total thyroxine (FT4 and T4), triiodothyronine (T3), thyroid-stimulating hormone (TSH) levels, and thyroid histology in normal Swiss albino female mice.Methods: Eighteen animals of 28–33 g were segregated into three groups: Group I treated with vehicle (NOR+VEH), Group II administered CN 400 mg/kg (NOR+CN 400), and Group III given CN 600 mg/kg (NOR+CN 600), for 15 days, per os (p.o.). The variation in the T4, FT4, T3, and TSH levels was recorded using ELISA, 24 h after the last dose, and T3/T4 ratio thus calculated along with the histopathological studies of the thyroid gland.Results: The findings were presented as mean ± standard error of the mean, using one-way ANOVA, followed by Dunnett’s post-tests to compare all columns with the control. NOR+CN 600 has shown thyroid protective effect through retaining euthyroid profile, normal T3/T4 ratio, and near-normal histology. However, NOR+CN 400 had shown the significant decline in T3/T4 ratio and pathological changes in thyroid histology, in comparison with the control and NOR+VEH group.Conclusion: The higher dose of CN was found to sustain the euthyroid levels through retention of iodothyronine deiodinases activity, facilitating the peripheral conversion of T4 to T3, and in retaining normal histoarchitecture of the thyroid gland in contrary to a lower dose.

Activity of antioxidant enzymes and processes of free radical oxidation in experimental hypothyroidism and correction of thyroid shifts with iodized polysaccharide complexes

Aim. To determine the activity of antioxidant enzymes in rat liver tissue on the background of thiamazole hypothyroidism, and also after its correction with iodine-containing organo-mineral complexes. Methods. Studies were conducted on rats, which were divided into four groups: the first group - the control, in animals of the second, third and fourth groups hypothyroidism was induced by daily intragastric administration of thiamazole at a dose 2.5 mg per 100 g body weight for the duration of 3 weeks. Beginning from the 22-day of the experiment the animals of the fourth group for the duration of a month received a biologically active additive in a dose that provides the daily requirement of iodine in rats, while the animals of the third group were on the standard diet of the vivarium. The activity of superoxide dismutase and glutathione peroxidase was determined using a set of reagents «RANSOD Randox» manufactured by «Laboratories Ltd.», the catalase activity was determined by the method of M.A. Korolyuk. Results. Experimental hypothyroidism in rats was characterized by a decrease in the concentrations of free thyroxine, an increase in the content of total triiodothyronine and thyroid-stimulating hormone. In animals treated with tiamazol, the superoxide dismutase activity was 85.6% of the activity level of the control animals, glutathione activity - 77.3% of the level of intact animals. The catalase activity in hypothyroidism decreased significantly - down to 40% of the control level (p ≤0.001). In the liver homogenate of rats, treated for 1 month with «iodine biopolymer» after hypothyroidism induction, the superoxide dismutase activity almost reached the control values and accounted for 95.5% of the activity of intact animals. The activity of glutathione peroxidase and catalase, was even slightly higher than the control values, reaching 115.6 and 112.7% of levels of activity in the control group, respectively (p ≤0,05). At the same time in the animals, which were on a standard diet, the activity of the studied enzymes remained below the control values, with the catalase activity - significantly lower (49.9% of the control, p ≤0,001). Conclusion. The introduction of an iodine-containing biologically active compound on the background of hypothyroidism made it possible to restore the activity of thyroid-dependant antioxidant enzymes, to normalize the functional state of the pituitary-thyroid system and to inhibit the processes of lipid peroxidation in the liver the of animals.

The Alteration of Coagulation in Patients with Thyroid Dysfunction

The influence of thyroid dysfunction on haemostasis is complex and still not very well understood. Both bleeding tendency and hypercoagulable states have been reported. In this article, we attempt to discuss the possible relationship between thyroid dysfunction and secondary haemostasis and fibrinolysis. After the analysis of the recent literature, we conclude that thyroid dysfunction is associated with alterations in fibrin generation and fibrinolysis. Most of the evidence suggests that hyperthyroidism is associated with impaired fibrinolysis and enhanced coagulation. Although, former studies proposed that there was an increase in fibrinolytic activity in hypothyroidism, increasing number of recent reports advocated the opposite. We believe that further prospective comprehensive clinical studies involving large numbers of patients either with overt or subclinical thyroid dysfunctions should be performed to clarify the effect of thyroid dysfunction on secondary haemostasis and fibrinolysis. Recent important patents focusing on coagulation and thyroid dysfunction are also discussed in this review.

Inhibition of pituitary type 2 deiodinase by reverse triiodothyronine does not alter thyroxine-induced inhibition of thyrotropin secretion in hypothyroid rats

Intrapituitary triiodothyronine (T3) production plays a pivotal role in the control of TSH secretion. Its production is increased in the presence of decreased serum thyroxine (T4) concentrations and the enzyme responsible, deiodinase type 2 (D2), is highest in hypothyroidism. In order to document the role of this enzyme in adult rats we developed an experimental model that inhibited this enzyme using the specific inhibitor, reverse T3 (rT3). Hypothyroidism was induced with propylthiouracil (PTU; 0.025 g/l in drinking water) which in addition blocked deiodinase type 1 (D1) activity, responsible for the rapid clearance of rT3 in vivo. During the last 7 days of the experiment, the hypothyroid rats were injected (s.c.) for 4 days with 0.4 or 0.8 nmol T4 per 100 g body weight (bw) per day. For the last 3 days, the same amount of T4 was infused via s.c. minipumps. In additional groups, 25 nmol rT3/100 g bw per day were added to the 3-day infusion of T4. Infusion of 0.4 nmol T4/100 g bw per day did not affect the high serum TSH levels, 0.8 nmol T4/100 g bw per day decreased them to 57% of the hypothyroid values. The infusions of rT3 inhibited D2 activity in all organs where it was measured: the pituitary, brain cortex and brown adipose tissue (BAT). In the pituitary, the activity was 27%, to less than 15% of the activity in hypothyroidism. Despite that, serum TSH levels did not increase, serum T4 concentrations did not change and the changes in serum T3 were minimal. We conclude that in partly hypothyroid rats, a 3-day inhibition of D2 activity, without concomitant change in serum T4 and minimal changes in serum T3 levels, is not able to upregulate TSH secretion and we postulate that this may be a reflection of absent or only minimal changes in circulating T3 concentrations.

The relation between plasma lipid levels and pseudocholinesterase activity in hypothyroidism.

The relation of plasma lipids and pseudocholinesterase (PChE) activity was studied in rats made hypothyroid by treatment with propylthiouracil (0.05% in drinking water for 28 days) and in hypothyroid patients prior and after L-thyroxine-therapy (1. week 25-50 microg, 2.-4. week 100 microg daily). In rats, thyroid hormone deficiency caused a significant increase in plasma and adipose tissue PChE activity as well as total plasma cholesterol (TC) concentration, and a decrease in plasma triglyceride (TG) concentration. In contrast to rats, thyroid-deficient humans demonstrated a decrease in plasma PChE activity and an increase in both TC and TG, in comparison with euthyroid controls. After one month's therapy with L-thyroxine, reversion of PChE activity and lipid concentrations occurred. The opposite changes of PChE elicited by thyroid hormone deficiency in men and rats are similar to the respective changes in lipoprotein lipase (LPL) activity, observed by other authors. The inverse correlation between both PChE and LPL activity and TG concentration suggests that PChE, similarly to LPL, may be involved in TG hydrolysis.

Alterations in carnitine–acylcarnitine translocase activity and in phospholipid composition in heart mitochondria from hypothyroid rats

Changes in mitochondrial fatty acid metabolism may underlie the decline in cardiac function in the hypothyroid animals. The effect of hypothyroidism on fatty acid oxidation, carnitine–acylcarnitine translocase activity and lipid composition in rat heart mitochondria has been examined. Rates of mitochondrial fatty acid oxidation as well as carnitine-carnitine and carnitine–palmitoylcarnitine exchange reactions were all depressed in heart mitochondria isolated from hypothyroid rats. Kinetic analysis of the carnitine–carnitine exchange reaction showed that the hypothyroid state affects the V max of this process, while having no effect on the K m value. Heart mitochondrial inner membrane lipid composition was significantly altered in hypothyroid rats. Cardiolipin, particularly, was found to decrease (by around 36%). Alterations in fatty acid pattern of mitochondrial inner membrane preparations from hypothyroid rats were also found. The effects of the hypothyroid state on fatty acids oxidation, carnitine translocase activity and phospholipid composition were completely reversed by following treatment of hypothyroid rats with thyroid hormone. A lower cardiolipin content in the mitochondrial inner membrane offers a plausible mechanism to explain the decline in the translocase activity in hypothyroidism.

Cholesterol 7αHydroxylase Activity in Hypothyroidism and Hyperthyroidism in Humans

Alterations of serum cholesterol levels are well recognized findings in hypothyroidism and hyperthyroidism. It remains unclear, whether thyroid hormones may affect serum concentrations of cholesterol through changes in the activity of cholesterol 7 alpha-hydroxylase, the rate-limiting enzyme in the catabolic conversion of cholesterol to bile acids. We determined serum concentrations of the bile acid precursor 7 alpha-hydroxy-4-cholesten-3-one, which reflects cholesterol 7 alpha-hydroxylase activity in the liver, in 19 patients with hypothyroidism and in 10 patients with hyperthyroidism before and after treatment, respectively. In patients with hypothyroidism, serum concentrations of cholesterol and LDL-cholesterol decreased by 33% (p < 0.0005) and 39% (p < 0.0005), respectively, after replacement therapy with thyroid hormones. In contrast, serum concentrations of 7 alpha-hydroxy-4-cholesten-3-one (21.7 +/- 15.8 ng/ml vs 24.5 +/- 18.1 ng/ml before treatment, n.s.) as well as serum HDL-cholesterol were unchanged during substitution therapy. In patients with hyperthyroidism, serum concentrations of cholesterol and LDL-cholesterol increased by 27% (p < 0.01) and 39% (p < 0.01) after antithyroid treatment, respectively. Again, serum concentrations of 7 alpha-hydroxy-4-cholesten-3-one did not change significantly during treatment (15.8 +/- 12.6 ng/ml vs 14.7 +/- 8.1 ng/ml before treatment, n.s.). These findings indicate that in humans, thyroid hormones influence serum lipid concentrations by other mechanisms than by affecting the activity of cholesterol 7 alpha-hydroxylase.

Parasympathetic nervous system activity in hypothyroidism determined by R‐R interval variations on electrocardiogram

Little is known about the relationship between hypothyroidism and the parasympathetic nervous system. R-R interval variations revealed by electrocardiogram (ECG) are known to be a useful clinical indicator of abnormalities of parasympathetic nervous system activity. Studies were conducted in hypothyroid patients, and significant reductions in R-R interval variations were observed in patients with primary severe hypothyroidism due to Hashimoto's thyroiditis, and in patients with Graves' disease who became severely hypothyroid during antithyroid drug therapy. R-R interval variations were restored to normal levels in both groups of patients after treatment. The present investigation suggests that in marked hypothyroidism there are hypofunctional abnormalities in the parasympathetic nervous system in association with a reduction in the levels of serum T4 and T3.

BAROREFLEX‐GOVERNED SYMPATHETIC OUTFLOW TO MUSCLE VASCULATURE IS INCREASED IN HYPOTHYROIDISM

Microelectrode recording of muscle nerve sympathetic activity (MSA), which is baroreflex-governed and involved in cardiovascular homeostasis, was made in five patients with hypothyroidism and in seven patients with hyperthyroidism prior to treatment and after recovery to euthyroidism. Patients with hypothyroidism had a higher level of MSA when hypothyroid than after recovery (mean +/- SEM 39.3 +/- 7.1 and 26.8 +/- 7.9 bursts/min, respectively, P less than 0.05), whereas hyperthyroidism was not accompanied by a change in the number of sympathetic bursts/min. The response of MSA to manouvres known to influence the neural outflow via baroreceptors and other receptor inputs was not changed with altered thyroid function. The findings provide direct evidence of an increased sympathetic activity in hypothyroidism, but suggest that other physiological properties of MSA are intact in thyroid disease.

Reduced serum carnosinase activity in hypothyroidism.

Carnosinase hydrolyses carnosine in muscle, and its deficiency is associated with extensive neuromuscular abnormalities. We measured serum carnosinase activity in patients with thyroid dysfunction which often involves neuromuscular systems. In hyperthyroidism, the carnosinase activity was not significantly different from that in normal subjects. In hypothyroidism, however, it was significantly lower than that in normal subjects. The activity examined in five patients with hypothyroidism returned to normal after replacement therapy. In hypothyroidism, the carnosinase activity showed significant correlation with concentration of serum thyroxine and negative correlation with serum creatine kinase activity. This finding may be of practical importance in the differential diagnosis of disorders causing carnosinase deficiency.

Prolactin as a marker of dopaminergic activity at different levels of thyroid function in man.

To investigate the hypothesis of an altered dopaminergic activity in hypothyroidism, seven patients without thyroid tissue were studied by means of three consecutive tests: an iv bolus of TRH (200 micrograms); a continuous iv infusion (5 mg during 30 min) of metoclopramide (MCP); and a second, post-MCP, iv bolus of TRH (200 micrograms). The study was performed three times: (A) without treatment; (B) on the 15th day while on L-T4 (150 micrograms i.d.); and (C) on the 30th day with the same treatment. Each time was a different situation of thyroid function; on the basis of basal serum TSH (P less than 0.001, A vs B vs C). The response of PRL to the first (non-primed) TRH, expressed as the sum of increments in ng/ml (mean +/- SE), was significantly higher in A (659 +/- 155) than in C (185 +/- 61). Individual PRL responses correlated with circulating T3 (P less than 0.02), but not with T4. A significant increase of PRL occurred after MCP in the three situations, but there were no differences among them. Likewise, the responses to the second (MCP-primed) TRH showed no differences. Although there was an expected high correlation (P less than 0.001) between basal TSH and circulating thyroid hormones, the maximal response of TSH to both non-primed and MCP-primed TRH was in B. After MCP, no measurable increase of TSH could be demonstrated at any of the three levels of thyroid function. These results do not support the hypothesis of an altered dopaminergic activity in hypothyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

Alterations of oxidative phosphorylation reactions in mitochondria isolated from hypothyroid rat liver.

Several parameters of oxidative phosphorylation reaction were studied in vitro in isolated liver mitochondria from hypothyroid rats. When succinate was employed as a respiratory substrate for mitochondria incubated in a mannitol/sucrose/phosphate buffer, and measurements were performed during initial additions of ADP, the magnitude of state 3 and state 4 respiration was not different between mitochondria from the hypothyroid and those from the control rats. During the course of repetitive additions of ADP and consequently of sequential transitions from state 4 to state 3 and back to state 4, mitochondria from hypothyroid animals showed a gradual decline in the rate of both state 3 and state 4 respiration whereas those from normal animals did not. The total succinate dehydrogenase activity was not different between the two types of mitochondria, and the decline in state 3 and state 4 respiration was not accompanied by any change in the apparent Km for ADP or in the corrected ADP/O ratio [Biochem. Biophys. Res. Commun. (1973) 53, 988]. The amount of oxygen consumed during the state-4----3----4 transition was lower in the hypothyroid than in the control mitochondria. These alterations were reversed if the hypothyroid animals were injected with thyroxine intraperitoneally (2 micrograms/100 g body weight) for 3 weeks before isolation of mitochondria. These results indicate that the fall of respiratory activity in hypothyroidism may result from the decrease not only of respiratory activities of state 3 and state 4, but also of the energy spent in the process of the state-4----3----4 transition, while the coupling efficiency per se remains normal. These properties become manifest when mitochondria respond to pulses of ADP load, a situation likely to occur in situ.

Selective effects of neonatal hypothyroidism on monoamine oxidase activities in the rat brain.

Hypothyroidism of mild intensity was obtained with prenatal and neonatal submission of Long-Evans rats to an iodide-rich diet. Chronic daily administration of methimazole to iodide-supplemented Long-Evans pups or to iodine-deprived Charles-River rats through the first 29-30 days of age provoked severe hypothyroidism. Monoamine oxidase type A (MAO-A) and not type B (MAO-B) activity was consistently, although slightly (by approximately 20%), increased in the hypothyroid brain. Triiodothyronine (T3)-induced hyperthyroidism did not affect MAO activity. Replacement therapy with T3 did not normalize MAO-A activity in hypothyroidism. Methimazole displayed a competitive and reversible in vitro inhibition of MAO-A but not MAO-B activity. Although this effect was obtained at concentrations far higher than those estimated to reach the brain after a single injection of the goiterogen, the occurrence of accumulation processes in the metabolism-deficient hypothyroid neonate rats cannot be excluded. Thus, MAO-A activity might be either directly depressed during the goiterogenic treatment, or increased as the result of some kind of rebound effect after interruption of methimazole administration.

Decreased serum alkaline phosphatase activity in hypothyroidism: possible relationship to low serum zinc and magnesium.

Decreased serum alkaline phosphatase activity in hypothyroidism: possible relationship to low serum zinc and magnesium.

Decreased Steroid Glucuronyl Transferase Activity in Hypothyroidism of Children Aged 1–6 Years

In 12 hypo- and 32 euthyroid children the distribution of urinary steroids on the fractions of free steroids(F), glucuronides(G), and sulfates(S) was studied. F, G, and S were separated on SEPHADEX LH-20 before cleavage of conjugates, steroids determined by capillary-GLC. Although G remained the main fraction in hypothyroidism the percentage of S and F was about twice as high as in euthyroid patients. especially after ACTH-stimulation. Apparently the decrease in glucuronyltransferase activity was more pronounced than that in the sulfotransferase system, a situation like in newborns, indicating retarded development rather, than, temporarilly reduced activity in hypothyroidism. The fact that it took more than 4 weeks after start of therapy with thyroid hormone for the %-distribution of steroids to equal that of healthy children supports this contention.

Decreased myocardial adenyl cyclase activity in hypothyroidism.

It has been suggested that hypothyroidism may alter the responsiveness of the heart to sympathetic stimulation. To define more precisely the interrelationship between hypothyroidism and catecholamine responsiveness we: (a) studied the effects of norepinephrine and fluoride on the activation of adenyl cyclase in the particulate fraction of heart homogenates from euthyroid and hypothyroid cats; and (b) assessed the contractile response of isolated right ventricular papillary muscles from the same cats to increasing concentrations of norepinephrine. It was found that maximal accumulation of cyclic 3',5'-adenosine monophosphate (3',5'-AMP) was significantly lower at peak norepinephrine concentrations in the hypothyroid (284 +/-5 pmoles) than in the euthyroid group (326 +/-10 pmoles) (P < 0.02). However, the K(m) for norepinephrine was similar in both groups (1-2 x 10(-5) moles/liter), and there was no apparent change in the threshold concentration. Fluoride-mediated increases in Cyclic 3',5'-AMP accumulation were also significantly lower in the hypothyroid (585 +/-25 pmoles) as compared to the euthyroid group (790 +/-20 pmoles) (P < 0.02). In contrast, norepinephrine produced a similar augmentation of contractility in isolated papillary muscles from the hypothyroid and euthyroid cats. It thus appears that although the hypothyroid state is associated with a decrease in the total amount of myocardial adenyl cyclase per milligram of tissue capable of being activated by norepinephrine or fluoride, there is no change in the sensitivity of the enzyme to norepinephrine stimulation. Moreover, the finding that the inotropic response to norepinephrine is unaltered in hypothyroidism is compatible with the hypothesis that only a fraction of the total intracellular cyclic 3',5'-AMP produced by norepinephrine activation of adenyl cyclase is required to elicit the inotropic response.