Thyroid Hormone Secretion Research Articles

Colloidal aggregates of insoluble inclusions in human goiters

To shed some light on the physicochemical properties of the thyroid follicular colloid, we have screened retrospectively the autoradiographs of 60 human nodular goiters labeled 17 h preoperatively with 100 μCi 125I for evidence of colloid compartmentalization. In 87% (52/60) of all goiters examined, sporadic or multiple colloidal inclusions (`colloid stones') not mixing with newly labeled Tg were detected. The detailed analysis of 17 goiters revealed a mean incidence of 0.09 ± 0.11 `colloid stones' of variable size per follicle ranging from 0.02 ± 0.01 (10) to 0.43 ± 0.09 (5) (mean values ± S.D., number of sections examined in brackets). In this study we did not find a clear-cut association of incidence of `colloid stones' with sex, age or nosologic group (hyperthyroid, preclinically hyperthyroid, euthyroid). The existence of different colloidal compartments as demonstrated in this and other studies is of considerable importance for thyroid function, interpretation of iodine kinetics, and studies on the role of iodine on growth and function of the thyrocytes. Different thyroidal iodine compartments could well be of functional relevance, for example in the adaptation of thyroid hormone secretion to antithyroid drugs or in severe and prolonged iodine deficiency, when very slow compartments become an important source of minimal quantities of iodine and thyroid hormone. `Colloid stones', for example, may well explain the repeatedly observed, surprisingly large total iodine store in human endemic goiters, even in the presence of severe iodine deficiency. It is evident that the existence of multiple iodine compartments and, in particular, of particulate slow-turnover pools complicates the interpretation of total glandular iodine measurements with modern techniques such as X-ray fluorescence and positron emission tomography.

Thyroglobulin regulates follicular function and heterogeneity by suppressing thyroid-specific gene expression

Thyroglobulin (TG) is the primary synthetic product of the thyroid and the macromolecular precursor of thyroid hormones. TG synthesis, iodination, storage in follicles, and lysosomal degradation can each modulate thyroid hormone formation and secretion into the circulation. Thyrotropin (TSH), via its receptor (the TSHR), increases thyroid hormone levels by upregulating expression of the sodium iodide symporter (NIS), thyroid peroxidase (TPO), and TG genes. TSH does this by modulating the expression and activity of the thyroid-specific transcription factors, thyroid transcription factor (TTF)-1, TTF-2, and Pax-8, which coordinately regulate NIS, TPO, TG, and the TSHR. Major histocompatibility complex (MHC) class I gene expression, which is also regulated by TTF-1 and Pax-8 in the thyroid, is simultaneously decreased; this maintains self tolerance in the face of TSH-increased gene products necessary for thyroid hormone formation. We now show that follicular TG, 27S > 19S > 12S, counter-regulates TSH-increased thyroid-specific gene transcription by suppressing the expression of the TTF-1, TTF-2, and Pax-8 genes. This decreases expression of the TG, TPO, NIS and TSHR genes, but increases class I expression. TG action involves an apical membrane TG-binding protein; however, it acts transcriptionally, targeting, for example, a sequence within 1.15 kb of the start of TTF-1 transcription. TG does not affect ubiquitous transcription factors regulating TG, TPO, NIS and/or TSHR gene expression. TG activity is not duplicated by thyroid hormones or iodide. We hypothesize that TG-initiated, transcriptional regulation of thyroid-restricted genes is a normal, feedback, compensatory mechanism which regulates follicular function, regulates thyroid hormone secretion, and contributes to follicular heterogeneity.

Productive, physiological and biochemical changes in imported and locally born Friesian and Holstein lactating cows under hot summer conditions of Egypt.

Twenty each of healthy lactating Friesian and Holstein cows were studied. They were of similar age and body weight, nonpregnant in their third lactation and 80-100 days post partum. The investigation was carried out for 8 weeks on two farms at the same time during the hot summer season in Egypt. The first farm was in Demietta (North east of the Nile Delta, 31 degrees 40' N) on 20 Friesian cows and the second was in Fakous (East of the Nile Delta, 30 degrees 40' N) on 20 Holstein cows. On each of the two farms, 10 cows were newly imported and 10 were born in Egypt. The average daily milk yield and total milk production in the third lactation of the newly imported cows were significantly higher than those of the locally born cows for both Friesians and Holsteins. At the same time, the T4, T3, urea-N, haematological values and AST enzyme activity in the newly imported cows were significantly lower than those in the locally born ones in both breeds, while the locally born cows showed significantly lower values for rectal temperature and respiration rate, as well as for AST and Alk-P enzyme activities, than the newly imported cows of either breed. Holstein cows surpassed the Friesians in milk production, as well as thyroid hormone secretion and cholesterol, haemoglobin, packed cell volume and erythrocyte count values. The opposite was found for serum total protein, urea-N and creatinine concentrations, leukocyte count and AST, ALT and Alk-P enzyme activities.

Thyroglobulin: A Master Regulator of Follicular Function via Transcriptional Suppression of Thyroid Specific Genes.

Thyroid gland function is thought to be tightly regulated by thyrotropin (TSH). However, the function of each thyroid follicle is heterogeneous despite having the same blood supply of TSH and despite homogeneous thyrocyte expression of the TSH receptor (TSHR). The nature of this heterogeneity is not fully understood. Recent studies showed that thyroglobulin (TG) protein, stored in the follicular lumen, is a potent negative feedback regulator of follicular function. Thus, physiological concentrations of TG significantly suppress thyroidspecific gene expression in cultured thyrocytes and antagonizes the maximal TSH stimulation of thyroid-specific genes: thyroglobulin, thyroid peroxidase, sodium iodide symporter and TSH receptor. In vivo studies are consistent with these results. This regulation is mediated by TG suppression of thyroid-specific transcription factors: thyroid-transcription factors 1 and 2 as well as Pax-8. We propose a model of follicular activity wherein each follicle has its own cycle of thyroid hormone synthesis and secretion and wherein follicular heterogeneity reflects the asynchronous function of individual follicles. We provide evidence that this mechanism may be related to the phenotype of some thyroid diseases.

Physiological regulation of hypothalamic TRH transcription in vivo is T3 receptor isoform specific.

Thyroid hormone (tri-iodo-thyronine, T3) exerts transcriptional effects on target genes in responsive cells. These effects are determined by DNA/protein interactions governed by the type of T3 receptors (TRs) in the cell. As TRs show tissue and developmental variations, regulation is best addressed in an integrated in vivo model. We examined TR subtype effects on thyrotropin-releasing hormone (TRH) transcription and on the pituitary/thyroid axis end point: thyroid hormone secretion. Polyethylenimine served to transfect a TRH-luciferase construct containing 554 bp of the rat TRH promoter into the hypothalami of newborn mice. Transcription from the TRH promoter was regulated in a physiologically faithful manner, being significantly increased in hypothyroidism and decreased in T3-treated animals. Moreover, when various ligand binding forms of mouse or chicken TRbeta and TRalpha were expressed with TRH-luciferase, all forms of TRbeta gave T3-dependent regulation of TRH transcription, whereas transcription was T3 insensitive with each TRalpha tested. Moreover, chicken TRalpha increased TRH transcription sixfold, whereas mouse TRalpha decreased transcription. These transcriptional effects had correlated physiological consequences: expression of the chicken TRalpha in the hypothalamus of newborn mice raised circulating T4 levels by fourfold, whereas mouse TRalpha had opposite effects. Thus, TR subtypes have distinct, physiologically relevant effects on TRH transcription.

From malnutrition to refeeding during anorexia nervosa

Anorexia nervosa is one of the most common forms of malnutrition observed in Western society in individuals without physical diseases, with an average risk of mortality of 20% in a younger population aged between 15 and 25 years. It is characterised by an initial dramatic decrease in food intake that leads to profound depletion in muscle and fat mass. During the course of the disease, the resting energy expenditure decreases proportionally to the loss of lean body mass with a decrease in thyroid hormone secretion. The metabolic adaptation during anorexia nervosa is similar to that observed during starvation with a relative sparing of protein stores. After an initial weight loss, the total energy expenditure is similar to that in normal individuals, with a decrease in resting energy expenditure and an increased energy-related physical activity. At the end stage of wasting, however, physical activity dramatically decreases as well as energy intake. This metabolic adaptation of semi-starvation is impaired during refeeding with an increase in the thermic effect of food and a high risk of refeeding syndrome with severe hypophosphatemia.

The neuropeptides, VIP and NPY, that are present in the thyroid nerves are not released into the thyroid vein.

In the present study, we tested the hypothesis that the neuropeptides, vasoactive intestinal peptide (VIP) and neuropeptide Y (NPY), which are present in the thyroid nerves, act as physiological neurotransmitters involved in the regulation of thyroid hormone secretion and thyroid blood flow. Specifically, we examined whether these neuropeptides can be released into thyroid blood vessels by electrical stimulation of the major thyroid nerves or whether their expression is altered by changes in iodine intake. Sprague-Dawley rats were used in this study. The cervical sympathetic trunk or the superior laryngeal nerve was stimulated by bipolar electrodes in anesthetized rats. During nerve stimulation, blood samples were withdrawn from the thyroid vein. Thyroid blood flow was monitored by laser Doppler blood flowmetry. Sympathetic stimulation caused a marked decrease in thyroid blood flow, which was associated with a significant increase in release of norepinephrine. However, these effects were not accompanied by any change in NPY release into the thyroid vein. Stimulation of the superior laryngeal nerve was not associated with changes in thyroid blood flow or VIP release into the thyroid vein. In a separate experiment, rats were fed a diet containing low-, high-, or normal iodine concentrations. Triiodothyronine (T3) and thyroxine (T4) levels in thyroid venous plasma were significantly reduced in rats fed a low-iodine diet but not in a separate group of rats fed a high iodine diet. However, these treatments had no effect on VIP or NPY concentrations in thyroid venous plasma or in thyroid ganglia. Thus, our results indicate that VIP and NPY, which are present in the thyroid nerves, may not be directly involved in the regulation of thyroid function.

Natural killer cell activity in patients with Graves' disease and Hashimoto's thyroiditis.

Natural killer (NK) cell activity of peripheral blood lymphocytes (PBL) against k562 human tumor cell targets was studied in patients with Graves' disease and Hashimoto's thyroiditis. NK activity was measured in a standard 4-hour 51chromium (Cr) release assay. Cytotoxicity was expressed as lytic units (LU)/10(6) PBL. Significantly decreased NK cell activity was demonstrated in both groups of patients, with mean (+/- SE) lytic units of 10.3 (+/- 9.1) and 13.3 (+/- 10.3) for patients with Graves' disease and Hashimoto's thyroiditis, respectively, compared with 36.0 (+/- 26.3) for age- and sex-matched normal subjects. When patients with Graves' disease were analyzed according to their thyroid status; NK activity was significantly depressed in (1) hyperthyroid patients before treatment; (2) hyperthyroid patients receiving antithyroid therapy; and (3) euthyroid patients receiving antithyroid therapy, compared with normal subjects. Graves' disease patients who were hypothyroid after radioactive iodine therapy or thyroidectomy had normal NK activity. No significant differences between hyperthyroid and euthyroid patients or between hypothyroid patients and normal subjects were demonstrated. NK activity in patients with Graves' disease did not correlate with serum levels of thyroxine, the presence or severity of ophthalmopathy, or titers of serum thyroid antibodies. In patients with Hashimoto's thyroiditis there was no correlation between NK activity and goiter size, titers of antithyroid antibodies, or thyroid status. These findings suggest that depression of NK activity in both disorders is secondary to abnormalities of thyroid hormone secretion, although an effect of the underlying autoimmune reactions has not been excluded.

Acute and delayed effects of a single-dose injection of interleukin-6 on thyroid function in healthy humans.

Interleukin-6 (IL-6) is produced in response to inflammatory and noninflammatory stress and acts as the principal regulator of the acute-phase protein response. IL-6 stimulates the hypothalamic-pituitary-adrenal axis and may be involved in the thyroid function abnormalities observed in nonthyroidal illness (NTI). This study examined the effects of single-dose IL-6 (3 microg/kg subcutaneously [s.c.]) in healthy human subjects: 19 received IL-6 and 13 received control saline injection. The dose of IL-6 was chosen on the basis of previous studies indicating that the peak IL-6 level after injection reaches concentrations observed with major stress such as abdominal surgery. Plasma levels of thyrotropin (TSH), free thyroxine (FT4), total T4, 3,5-3'-L-triiodothyronine (T3), 3,3'-5'-L-triiodothyronine or reverse T3 (rT3), and thyroxine-binding globulin (TBG) were measured over a 4-hour period and 24 hours after IL-6 injection. Plasma TSH levels were 27% lower 240 minutes after IL-6 relative to control levels (0.93 +/- 0.10 v 1.28 +/- 0.18 mIU/mL, P = .001), but recovered by 24 hours. Plasma FT4 was elevated at 240 minutes compared with the controls (1.16 +/- 0.04 v 1.03 +/- 0.03 ng/dL, P = .0002). T4 levels were also elevated at 240 minutes (7.8 +/- 0.36 v 7.05 +/- 0.37 microg/dL, P = .0003). TBG levels were not significantly changed at this time point. At 24 hours, T3 levels were 19% lower than the control values (87.6 +/- 5.1 v 108.5 +/- 5.4 ng/dL, P = .0002); plasma rT3 levels were elevated by 21% compared with control levels (30.6 +/- 1.7 v 24.3 +/- 1.3 ng/dL, P = .002), while FT4 levels returned to normal. The changes in T3/rT3 levels were reminiscent of the pattern observed in NTI that may be due to inhibition of type-1 5'-deiodinase. Cortisol levels were greatly elevated after IL-6 compared with control values; peak levels were observed 120 minutes after IL-6 injection (28.7 +/- 1.6 v 9.5 +/- 1.0 ng/dL, P < .0001). This elevation in cortisol may have contributed to the suppression of TSH levels and inhibition of type-1 5'-deiodinase activity. Alternatively, IL-6 may have suppressed TSH secretion via a direct suprapituitary action. The elevation of T4 and FT4 levels may have been due to inhibition of T4 degradation at the liver and/or by direct action of IL-6 on the thyroid gland. These findings demonstrate the potent effects of IL-6 on thyroid hormone metabolism in healthy individuals, and suggest that IL-6 may act directly or indirectly at two or more sites on thyroid hormone secretion and metabolism.

The effects of lithium therapy on thyroid and thyrotropin-releasing hormone.

Lithium is used in the prophylaxis of bipolar depressive disorder in augmentation treatment of depression and in the therapy of some cases of unipolar depression. Lithium affects cell function via its inhibitory action on adenosine triphosphatase (ATPase) activity, cyclic adenosine monophosphate (cAMP), and intracellular enzymes. The inhibitory effect of lithium on inositol phospholipid metabolism affects signal transduction and may account for part of the action of the cation in manic depression. Lithium also alters the in vitro response of cultured cells to thyrotropin-releasing hormone (TRH) and can stimulate DNA synthesis. Lithium is concentrated by the thyroid and inhibits thyroidal iodine uptake. It also inhibits iodotyrosine coupling, alters thyroglobulin structure, and inhibits thyroid hormone secretion. The latter effect is critical to the development of hypothyroidism and goiter. Effects on brain deiodinase enzymes and alterations in thyroid hormone receptor concentration in the hypothalamus are under investigation in relation to the therapeutic effect of lithium. The ion affects many aspects of cellular and humoral immunity in vitro and in vivo. This accounts for a rise in antithyroid antibody titer in patients having these antibodies before lithium administration whereas there is no induction of thyroid antibody synthesis de novo. Goiter, due to increased thyrotropin (TSH) after inhibition of thyroid hormone release, occurs at various reported incidence rates from 0%-60% and is smooth and nontender. Subclinical and clinical hypothyroidism due to lithium is usually associated with circulating anti-thyroid peroxidase (TPO) antibodies but may occur in their absence. Iodine exposure, dietary goitrogens, and immunogenetic background may all contribute to the occurrence of goiter and hypothyroidism during long-term lithium therapy. It is currently unclear whether the reported association of lithium therapy and hyperthyroidism are causal, although there is suggestive epidemiological evidence. Finally, lithium therapy is associated with exaggerated response of both TSH and prolactin to TRH in 50%-100% of patients, although basal levels are not usually high. It is probable that the hypothalamic pituitary axis adjusts to a new setting in patients receiving lithium.

Environmental modulation of the immune system via the endocrine system

Numerous studies have demonstrated that a variety of hormones have receptors and exert biologic actions on tissues of the immune system. Conversely, cytokines exert biologic actions on the endocrine system. This bidirectional interaction is likely involved in maintenance of physiological and immunologic homeostasis. This paper summarizes a variety of actions of growth hormone (GH), prolactin (PRL), insulin-like growth factor-I (IGF-I), glucocorticoids and thyroid hormones (TH) on the immune system. It then proceeds to put these actions into a hypothetical context whereby these hormones may mediate some changes in immune system function in response to environmental stimuli such as physical and emotional stress, nutritional deprivation and environmental temperature. In the first example, it is proposed that PRL secretion in response to stress may serve an immunomodulatory role in two ways. The first is by stimulating the immune system directly and the second is by dampening or reducing the degree to which glucocorticoids are secreted in response to stress. The second example suggests that the increase in GH secretion and reduced IGF-I secretion in response to protein/energy restriction may have two potential immunomodulatory actions. One action is a direct effect of GH on several components of the immune system. The other is the partitioning of nutrient use away from skeletal muscle growth and toward tissues of higher priority such as the immune system. The third example proposes that the increased secretion of TH during cold environmental temperatures not only increases basic metabolic rate, but also directly stimulates both primary and secondary lymphoid tissues. It is suggested, therefore, that these three hormones are involved in maintaining immune system homeostasis in response to environmental change.

Effects of exogenous triiodothyronine (T 3) and a goitrogen, methylthiouracil (MTU), on thyroid gland function in sheep

The rationale that conjoint use of feedback inhibition could alter the effectiveness of a goitrogen, methylthiouracil (MTU), for achieving pharmacological suppression of thyroid gland function was tested in sheep. Experiment 1 determined the appropriate daily dose of T 3 for achieving feedback suppression of thyroid secretion. Experiment 2 tested the hypothesis that prior treatment with T 3 at such dosage would speed up the thyroid suppressive effect of subsequent administration of MTU, and Experiment 3 determined whether T 3 exerted feedback inhibition on the anterior pituitary gland. In Experiment 1, ewes ( n=6) treated with doses of 0, 1, 5 and 25 μg T 3 per kg live weight as a daily s.c. injection for 2 weeks had a dose-related increase in heart rate and decrease in plasma T 4 concentration. Ewes in Experiment 2 received combinations of daily s.c. injections of T 3 at 5 μg per kg and daily oral dosing with 35 mg per kg MTU ( n=6). Suppression of plasma T 4 concentration by T 3 did not improve the effect of subsequent treatment with MTU. In Experiment 3, plasma TSH responses to TRH stimulation (200 μg, i.v.) were reduced by treatment with T 3, confirming its feedback inhibition of the anterior pituitary gland. It is concluded that, in spite of the inhibitory actions of T 3 on plasma T 4 concentration in sheep, its use prior to treatment with MTU did not affect the resultant suppression of thyroid hormone secretion.

Autoregulation of thyroid-specific gene transcription by thyroglobulin.

Thyroglobulin (TG), the primary synthetic product of the thyroid, is the macromolecular precursor of thyroid hormones. TG synthesis, iodination, storage in follicles, and degradation control thyroid hormone formation and secretion into the circulation. Thyrotropin (TSH), via its receptor (TSHR), increases thyroid hormone levels by up-regulating expression of the sodium iodide symporter (NIS), thyroid peroxidase (TPO), and TG genes. TSH does this by modulating the expression and activity of several thyroid-specific transcription factors, thyroid transcription factor (TTF)-1, TTF-2, and Pax-8, which coordinately regulate NIS, TPO, TG, and the TSHR. Major histocompatibility complex class I gene expression, which also is regulated by TTF-1 and Pax-8 in the thyroid, is decreased simultaneously. This helps maintain self-tolerance in the face of TSH-increased gene products necessary for thyroid hormone formation. In this report we show that follicular TG counter-regulates TSH-increased, thyroid-specific gene transcription by suppressing expression of the TTF-1, TTF-2, and Pax-8 genes. This decreases expression of the TG, TPO, NIS, and TSHR genes, but increases class I expression. TG acts transcriptionally, targeting, for example, a sequence within 1.15 kb of the 5' flanking region of TTF-1. TG does not affect ubiquitous transcription factors regulating TG, TPO, NIS, and/or TSHR gene expression. The inhibitory effect of TG on gene expression is not duplicated by thyroid hormones or iodide and may be mediated by a TG-binding protein on the apical membrane. We hypothesize that TG-initiated, transcriptional regulation of thyroid-restricted genes is a normal, feedback, compensatory mechanism that limits follicular function and contributes to follicular heterogeneity.

Prostate-thyroid axis: stimulatory effects of ventral prostate secretions on thyroid function.

Endocrine cells of the prostate secrete thyrotropin (TSH)-releasing hormone (TRH), TRH- and TSH-like peptides, and growth factors. Propylthiouracil- and methimazole-induced hypothyroidism increased prostatic levels of TRH in rats as in hypothalamus, whereas thyroxine (T4) replacement decreased TRH. From these reports, we inferred the existence of a prostate-thyroid axis. The influence of the prostate on the thyroid gland was studied in albino rats. Ventral prostate was surgically removed on day 31 postpartum. The animals were sacrificed on day 60 postoperation. Serum thyroid hormones were assayed by radioimmunoassay (RIA). For in vitro studies, normal thyroid and ventral prostate glands were cocultured with or without thyroid-stimulating hormone (TSH) antibody, to assess the direct influence of prostatic secretions on thyroid hormone secretion. Serum total and free T4 and triiodothyronine (T3) were significantly reduced in ventral prostatectomized rats. Histological analysis of the thyroid showed that the diameters of the peripheral and middle follicles, colloid epithelial cells, and nuclei were increased in prostatectomized rats, indicating hypothyroid status. Total T3 and T4 were significantly elevated in the culture medium when thyroid and prostate were cocultured, irrespective of the presence of TSH antibody. The present study suggests that ventral prostatic secretions have a stimulatory role on the thyroid gland.

Activating mutations of the thyrotropin receptor: a short review with emphasis on some pediatric aspects.

ten times higher than the cAMP pathway (9‐11). The cAMP pathway has been shown to be important for the positive control of thyroid hormone secretion and growth of the thyrocytes, whereas the inositol phosphate pathway seems mostly involved in the control of iodination and hormone synthesis (2, 12). Since the TSH receptor has a central role in the control of human thyroid follicular cell proliferation and function, it is therefore expected that its deregulation would lead to pathological processes.

Thyroid Disease

Part 1 Historical introduction: thyroidology - reflections on 20th century history. Part 2 Basic clinical sciences: surgical anatomy and embryology of the lower neck and superior mediastinum physiology of thyroid hormone synthesis, secretion and transport clinical approach to thyroid function testing parathyroid function and calcium homeostasis pathology of thyroid disease fine needle biopsy of the thyroid uptake tests, thyroid and whole body imaging with isotopes diagnostic imaging of the thyroid gland. Part 3 Molecuar biology of the thyroid gland: molecular basis of thyroid disease molecular biology of the TSH receptor thyroid hormone resistance syndromes oncogenes and thyroid cancer. Part 4 Hyperthyroidism: hyperthyroidism - systematic effects and differential diagnosis medical management of hyperthyroidism - theoretical and practical aspects treatment of hyperthyroidism with 131-I surgical treatment of hyperthyroidism thyroid-associated ophthalmology - aetiology and pathogenesis thyroid associated ophthalmology - treatment. Part 5 Hypothyroidism: clinical manifestations and differential diagnosis of hypothyroidism. Part 6 Thyroiditis - nodular and congenital thyroid disease: thyroiditis solitary thyroid nodule - concepts in diagnosis and treatment multinodular goiter management of substernal thyroid disease management of thyroid disorders involving the airway congential thyroid cysts and ectopic thyroid. Part 7 Treatment with thyroid hormone: replacement and suppressive treatment with thyroid hormone. Part 8 Thyroid cancer: thyroid cancer - controversies and aetiopathogenesis evaluation and surgical treatment of papillary and follicular carcinoma thyroglobulin in benign and malignant thyroid disease 131-I and external radiation in the treatment of local metastic thyroid cancer medullary and thyroid carcinoma and the multiple endocrine neoplasia syndromes anaplastic carcinoma, lymphona and the unusual malignancies, and chemotherapy for thyroid cancer management of thyroid carcinoma invading the upper aerodigestive system. Part 9 Surgery of the thyroid gland: general and regional anaesthesia for thyroid surgery the technique of thyroidectomy by cervical and thoracic approaches complications of thyroid surgery - an overview nonmetabolic complications of thyroid surgery metabolic complications of thyroid surgery metabolic complications of thyroid surgery - thyrotoxic storm.

Acute effects of chundosunbup qi-training on blood concentrations of TSH, calcitonin, PTH and thyroid hormones in elderly subjects.

The present study investigated how the systemic treatment of a programmed exercise, ChunDoSunBup (CDSB) Qi-training, affects the secretion of thyroid and parathyroid hormones in elderly subjects (10 male and 5 female). Plasma concentrations of thyroid stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), parathyroid hormone (PTH), ionized calcium, and calcitonin were determined. CDSB Qi-training induces a slight increase in TSH. Both T4 and T3 were increased at the mid-time of CDSB Qi-training (p < 0.05). There were significant correlations only between T3 and T4 at mid-training. This shows that increase in the plasma level of T3 was associated with the secretion of T4. The plasma concentrations of calcitonin and PTH were increased at mid-time and post-time of CDSB Qi-training. But ionized calcium was decreased slightly by CDSB Qi-training. These results suggest that Qi-training modulates the secretion of thyroid hormones, calcium metabolism, and parathyroid hormones in the elderly. However, whether the long-term practice of CDSB Qi-training might change bone metabolism and have longitudinal effects on the thyroid hormone of the elderly need further investigation.

Antigen-presenting dendritic cells as regulators of the growth of thyrocytes: a role of interleukin-1beta and interleukin-6.

An accumulation of antigen-presenting dendritic cells (DC) in the thyroid gland, followed by thyroid autoimmune reactivity, occurs in normal Wistar rats during iodine deficiency, and spontaneously in diabetic-prone Biobreeding rats. This intrathyroidal DC accumulation coincides with an enhanced growth rate and metabolism of the thyrocytes, suggesting that both phenomena are related. Because DC are known to regulate the hormone synthesis and growth in other endocrine systems (i.e. the pituitary, the ovary, and the testis), we tested the hypothesis that DC, known for their superb accessory cell function in T cell stimulation, act as regulators of thyrocyte proliferation (and hormone secretion). We investigated the effect of (Nycodenz density gradient) purified splenic DC from Wistar rats on the growth rate of and thyroid hormone secretion by Wistar thyroid follicles (collagenase dispersion) in culture. Various numbers of DC and follicles were cocultured during 24 h. The proliferative capacity of thyrocytes was measured by adding tritiated thymidine (3H-TdR) and bromodeoxyuridine, the hormone secretion into the culture fluid was measured by using a conventional T3 RIA. Furthermore, antibodies directed against interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) were added to these cocultures to determine the role of these cytokines in a possible DC regulation of thyrocyte growth. Cocultures were also carried out in the presence of antimajor histocompatibility complex-class I (MHC I), anti-MHC II, antiintercellular adhesion molecule-1 (ICAM-1), and antilymphocyte function-associated antigen-1alpha (LFA-1alpha) antibodies to possibly interfere with DC-thyrocyte interactions. The addition of DC to thyroid follicles clearly inhibited their 3H-TdR uptake, particularly at a 10:1 ratio, in comparison to follicle cultures alone, both under basal conditions and after TSH stimulation (75 +/- 7% and 49 +/- 11% reduction, respectively, n = 4). The follicle T3 secretion (after TSH stimulation) was also suppressed by DC in this system, but to a lesser extent (at best at an 1:1 ratio, 25 +/- 7% reduction, n = 4). The DC-induced inhibition of thyroid follicle growth was totally abrogated after addition of anti-IL-1beta antibodies; anti-IL-6 only had effect on the DC inhibition of non-TSH-stimulated thyrocytes, whereas anti-TNF-alpha demonstrated no effect at all. The antibodies to MHC and to adhesion molecules had also no effect on this DC-induced growth inhibition. The effect of the different anti-cytokine and anti-adhesion antibodies on the T3 secretion from thyroid follicles was not investigated. The clear inhibition of thyrocyte growth by splenic DC (classical antigen-presenting cells) again demonstrates the regulatory role of DC in endocrine systems. Proinflammatory cytokines such as IL-1beta and IL-6 are important mediators in this regulation. The here shown dual role of DC represents a link between the immune and endocrine system, which may form the gateway to the understanding of the initiation of thyroid autoimmune reactions and the thyroid autoimmune phenomena seen in iodine deficiency.

Desialylated and deglycosylated human chorionic gonadotropin are superagonists of native human chorionic gonadotropin in human thyroid follicles.

Highly purified human chorionic gonadotropin (hCG) interacts with the thyrotropin (TSH) receptor and stimulates triiodothyronine (T3) secretion, iodide uptake and organification, and cyclic adenosine monophosphate (cAMP) formation in human thyroid follicles. Because of interest in the role of the carbohydrate component in the structure-function relationships of hCG we undertook to deplete hCG of its sialic acid or carbohydrate residues and assess the thyrotropic activity of the carbohydrate-modified forms. For this purpose, we used our assay system consisting of human thyroid follicles cultured and suspended in collagen gel in serum-free medium. Under these conditions, the cells are organized as follicular three-dimensional structures with normal polarity, enabling enhanced responsiveness to hormonal stimulation, and T3 secretion can be measured as a response parameter. Desialylated (ds)-hCG and deglycosylated (dg)-hCG dose-dependently stimulated T3 secretion, iodide uptake and organification, and in each case did so with about twice the intrinsic activity of native hCG. Indeed, removal of the sialic acid or carbohydrate residues from native hCG transformed it into a thyroid stimulator that elicited a maximal response in terms of iodide uptake, organification and T3 secretion by human thyroid follicles as high as TSH and almost twice as high as native hCG. Not only were ds-hCG and dg-hCG more intrinsically active than hCG, they were more than five times as potent. As with hCG, both ds-hCG and dg-hCG managed to elicit such responses in human thyrocytes while evoking minimal amounts of cAMP, illustrating the concept of cAMP superfluity and highlighting the potential pitfalls of using cAMP as a measure of hormonal bioactivity. hCG, and to a greater extent ds-hCG and dg-hCG, inhibited, as did TSH, gamma-interferon-induced human leukocyte antigen-DR (HLA-DR) expression in human thyrocytes, again reflecting the intrinsic thyrotropic activity of native hCG and its variants depleted of sialic acid or carbohydrate residues. In conclusion, this is the first report on the thyrotropic activity of ds-hCG and dg-hCG using the physiologically relevant hormonal end-point response, thyroid hormone secretion. The study was conducted in a serum-free culture system of human thyroid follicles and shows that removal of the sialic acid or carbohydrate residues from native hCG transform hCG variants into thyroid stimulating superagonists. The hCG variants inhibited, as did TSH, gamma-interferon-induced HLA-DR expression.

Cloning and Expression of a Brain-Derived TSH Receptor

Several hormones not only regulate the activity of endocrine cells and non-endocrine tissues but also serve as neuronal transmitters or modulators of neuronal activity. Accordingly, the expression and physiological significance of hormonal receptors in the central nervous system (CNS) could be demonstrated for a whole set of hormones (e. g. hCG/LH, GH, T3, CRF, TRH). The G-protein coupled TSH receptor is densely expressed in the thyroid gland and mediates the production and secretion of thyroid hormones. Not all TSH effects, especially in neurological and psychiatric disease states, can readily be explained by the action of the hormone on the thyroid gland and/or TRH levels. Therefore, it has been suggested that TSH might exert its effects directly in the CNS, although no direct proof for a TSH receptor in the human brain has been provided yet. Here we describe the cloning of a TSH receptor from an ovine hypothalamic cDNA library that is similar to thyroid derived cDNA clones. The comparison of amino acid sequences indicates that several protein domains important for the function and activity of the receptor are highly conserved. RT-PCR and RNA protection assay demonstrated that the TSH receptor mRNA is widely expressed throughout the ovine brain. The expression of a TSH receptor in the CNS indicates that TSH is not only a hormonal messenger for the thyroid gland but can also act directly in the brain. Further studies should focus on the physiological role of TSH in the CNS and the regulation of TSH receptor expression in the mammalian brain.