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At least 19 recordsLinked to original sources
PubMed1999

Comparison of recombinant human thyrotropin receptors versus porcine thyrotropin receptors in the thyrotropin binding inhibition assay for thyrotropin receptor autoantibodies.

Thyrotropin receptor autoantibodies (TRAb) are most commonly measured in a thyrotropin-binding inhibition (TBI) assay using solubilized porcine thyrotropin receptors (pTSHR). Recently, we reported modifications in recombinant human thyrotropin receptor (hTSHR) production and extraction that made substitution of this antigen for the pTSHR practical. We now report the first comparison of the behavior in a TBI assay of the recombinant, solubilized hTSHR with the pTSHR in a large series of clinically characterized patients with autoimmune thyroid disease. We studied 227 patients with Graves' disease (32 untreated patients, 156 patients receiving antithyroid medications, 24 patients in remission, 9 patients with recurrence of disease, and 6 thyroidectomized patients), as well as 32 patients with Hashimoto's thyroiditis and 28 normal individuals. In patients with untreated Graves' disease, 29 of 32 (90.6%) were TBI positive with either antigen, although two sera gave discrepant data in the two assay. Of the patients receiving antithyroid drugs, 94 of 156 (60.3%) were positive with the pTSHR and 106 of 156 (67.9%) were positive with the hTSHR TBI assay (p < 0.05%). In all other respects, however, there was no difference between the two TBI assays. Neither assay performed well in providing clinical guidance in the remission or relapse of disease. Of the 24 Graves' patients in remission, 75.0% and 79.2% were TBI negative with the hTSHR and pTSHR assays, respectively. The TBI assay at the time of relapse was even less informative; 6 of 9 (66.7%) being TBI negative in the pTSHR assay and 3/9 (33.3%) being negative in the hTSHR assay. In TBI assays with both species of TSHR, 3 of 32 hypothyroid patients with Hashimoto's thyroiditis were TBI positive. In summary, production of the recombinant hTSHR is now a practical reality and this antigen can clearly substitute at least as well for the pTSHR in the imperfect, although most commonly used, TBI assay. It is, therefore, likely that the hTSHR will supplant the pTSHR in this important assay. However, the use of the hTSHR rather than pTSHR does not appear to provide a major advantage, at least in terms of TBI assay sensitivity, specificity and predictive value.

Animals↗
PubMed1975

Thyrotropin receptors in thyroid plasma membranes. Characteristics of thyrotropin binding and solubilization of thyrotropin receptor activity by tryptic digestion.

Biologically active bovine 125I-thyrotropin preparations have been prepared, characterized, and used to evaluate the optimal conditions for thyrotropin binding to bovine thyroid plasma membranes in vitro. Binding of 125I-TSH has a pH optimum around 6.0 and is sensitive to the choice and concentration of buffer. Binding is inhibited by salts, especially those containing magnesium and calcium ions; magnesium concentrations optimal for adenylate cyclase assays (2 to 5 mM) result in 85 to 98% inhibition of binding. Binding is temperature sensitive. At 37 degrees binding has its highest initial level; however, instability of the membrane at this temperature causes a rapid loss of binding activity. Binding at 0 degrees is optimal in 30 min and at the same level as initial binding at 37 degrees; since there is no decrease in binding activity, it has been chosen as the optimal temperature. Thyrotropin, luteinizing hormone, the beta subunit of thyrotropin, and the alpha subunit of thyrotropin have relative binding affinities for the thyrotropin receptors of 100, 10, 2, and less than 0.5, respectively. In all of these characteristics, 125I-thyrotropin at 1.5 x 10(-5) M concentrations has the same properties of binding to bovine plasma membranes as do [3H]thyrotropin preparations which have been previously characterized (Amir, S.M., Carraway, T.F., Jr., Kohn, L.D., and Winand, R.V. (1973) J. Biol. Chem. 248, 4092-4100) and used to study binding at 5 x 10(-6) M concentrations. 125I-TSH binding as a function of hormone concentration results in curved Scatchard plots; however, Hill plots of these same binding data are linear and have a slope of 0.65. Taken together, these data suggest that the heterogeneity in thyrotropin binding constants which is evident in the Scatchard plot reflects a negatively cooperative relationship among the thyrotropin receptor sites, i.e. decreased hormonal affinity as hormone concentrations increase. Adenylate cyclase studies yield kinetic plots which also exhibit negative cooperativity; corrections for thyrotropin bound under the adverse binding conditions of the adenylate cyclase assays suggest that Km values for thyrotropin in this enzymatic assay are compatible with binding constants measured by the 125I-thyrotropin preparations. Tryptic digestion destroys binding activity on the thyroid plasma membrane but releases specific thyrotropin receptor activity into the supernatant phase. Chromatography on Sephadex G-100 indicates that this solubilized receptor fragment has a molecular weight between 15,000 and 30,000.

Adenylyl Cyclases↗
PubMed1990

Thyrotropin receptor gene expression in oncogene-transfected rat thyroid cells: correlation between transformation, loss of thyrotropin-dependent growth, and loss of thyrotropin receptor gene expression.

Rat FRTL-5 and PC-Cl-3 thyroid cells are continuously cultured, clonal lines which require thyrotropin to grow and function. Both can be efficiently transformed when infected with RNA or DNA viruses carrying oncogenes or when directly transfected with activated oncogenes. Transformation, assayed by the appearance of cell growth in agar and by tumorigenicity in syngeneic rats or nude mice, is associated with the loss of thyrotropin-dependent cell division and thyrotropin-regulated functions such as thyroglobulin synthesis. In 16 clones of FRTL-5 or PC-Cl-3 cells transformed with different oncogenes, we show that loss of thyrotropin-dependent growth and function correlates with the loss of thyrotropin receptor gene expression, measured with a rat thyrotropin receptor cDNA probe.

Animals↗
PubMed1987

Interaction of the thyrotropin receptor on rat FRTL-5 thyroid cells with thyrotropin and a thyrotropin-stimulating autoantibody from Graves' patients.

FRTL-5 rat thyroid cells were either surface-labeled with 125I or biosynthetically labeled with [3H]N-acetylglucosamine, solubilized by lithium diiodosalicylate and immunoprecipitated after sequential exposure to bovine thyrotropin and anti-bovine thyrotropin. Autoradiography of polyacrylamide gels run under denaturing conditions and in the presence of a reducing agent revealed two prominent bands with approximate molecular weights of 66-70 kDa and 47 kDa. Immunoprecipitation of the same radiolabeled and solubilized membrane preparations with a Graves' disease IgG having thyroid stimulating but no thyrotropin-binding inhibiting activity revealed only one major band, migrating near the 47 kDa component reactive with thyrotropin. No bands were immunoprecipitated in control incubations using normal human IgG or substituting radiolabeled, solubilized membranes from a rat thyroid cell line with no thyrotropin receptor activity. Thin layer chromatography of Folch extracts of the [3H]-N-acetylglucosamine-labeled immunoprecipitates obtained by either procedure indicated that a specific thyroid ganglioside was coprecipitated with the immunoprecipitated proteins in both cases.

Animals↗
PubMed1975

Thyrotropin effects on thyroid cells in culture. Effects of trypsin on the thyrotropin receptor and on thyrotropin-mediated cyclic 3':5'-AMP changes.

Dog, human, and bovine thyroid cells in culture have been shown to develop follicle-like structures when cells are cultured in conditions of confluency and when cells are incubated in the presence of bovine thyrotropin or N6,O2'-dibutyryl cyclic adenosine 3':5'-monophosphate during the first 24 to 48 hours after trypsinization. If thyrotropin is added 48 hours after trypsinization, these cells do not form follicle-like structures but remain as a monolayer culture. Although thyroid cells which grow as a monolayer have a thyrotropin receptor on their plasma membranes with the same in vitro binding properties as the thyrotropin receptor on the plasma membranes of the follicle-forming thyroid cells, there is a 1- to 2-fold greater number of receptors per mg of membrane protein when follicle-forming and monolayer cultures are compared...

Animals↗
PubMed2000

The thyrotropin receptor is not involved in the activation of p42/p44 mitogen-activated protein kinases by thyrotropin preparations in Chinese hamster ovary cells expressing the human thyrotropin receptor.

We studied whether bovine pituitary thyrotropin (bTSH) or human recombinant thyrotropin (rhTSH) stimulated p42/p44 mitogen-activated protein kinases (MAPKs) in Chinese hamster ovary cells expressing human thyrotropin receptor (CHO-hTSHR cells). We show that p42/p44 MAPK phosphorylation was induced by both TSH preparations at similar levels in CHO-hTSHR cells and in wild-type CHO cells. In contrast, cyclic adenosine monophosphate (cAMP) production was stimulated by TSH only in CHO-hTSHR cells, demonstrating that p42/p44 MAPK stimulation was independent of the TSH receptor. Moreover, similar results were obtained with two other cell lines: the FRTL-5 thyroid cell line and the CCL39 fibroblast cell line. Maximal stimulation of p42/p44 MAPK phosphorylation was observed after a 5- to 10-minute incubation with bTSH and rhTSH preparations. At this time, the phosphorylation of GST-Elk1 was also increased in a time- and concentration-dependent manner by bTSH preparations. The phosphorylation of p42/p44 MAPKs was abolished by PD 98059 and GF 109203X, indicating the involvement of MAPK kinases (MEK 1/2) and protein kinase C. In contrast, the activation of p42/p44 MAPKs was insensitive to H89, to cholera toxin and to pertussis toxin. These data suggest that the protein kinase A pathway was not implicated in p42/p44 MAPK activation by TSH preparations. Moreover, Gs or Gi/Go proteins do not appear to participate in p42/p44 MAPK activation. We also showed that these TSH preparations failed to induce activation of c-Jun NH2 terminal kinase. We therefore conclude that the commercial TSH preparations used in this study contained factor(s) responsible for the specific activation of p42/p44 MAPKs by a TSH receptor-independent mechanism.

Animals↗
PubMed1979

Plasma thyrotropin-releasing hormone, prolactin, thyrotropin, and thyroxine concentrations following the intravenous or oral administration of thyrotropin-releasing hormone.

In a further evaluation of the use of oral thyrotropin-releasing hormone (TRH) in puerperally lactating women, a radioimmunoassay for its measurement has been developed. Its concentration in plasma as well as that of prolactin (PRL), thyrotropin (TSH) and thyroxine (T4) were measured following either intravenous or oral administration of TRH. Basal concentrations of TRH in 14 normally cycling women ranged from less than 5 to 17 pg/ml. Two luteal phase studies produced peaks in plasma TRH 5 to 10 minutes after 100 micrograms of TRH administered intravenously with a return to basal concentrations within 2 to 3 hours. In 10 normally menstruating women, ingestion of 10 mg of TRH orally resulted in plasma TRH which peaked at 423 +/- 123 pg/ml (standard error of the mean) at 30-minutes. Plasma PRL, TSH, and T4 also increased and remained slightly elevated at 4 hours. These 8-hour studies were performed in a puerperal lactating woman who had ingested 10 mg of TRH orally twice a day for 7 days prior to blood sampling. TRH concentrations declined throughout each day while TSH rose slightly in the first 1 to 2 hours but remained within normal limits. The prolonged administration of 10 mg of TRH orally twice daily to three puerperally lactating women resulted in elevations in plasma TRH 2 to 3 hours following hormone administration, yet no significant increases in plasma TSH were observed. Both endogenous TRH and TSH were measured before and after 22 nursing events in nine puerperally lactating women. There was no change in the concentration of either substance and all values were similar to those obtained in normally menstruating women.

Administration, Oral↗
PubMed1986

In vitro effects of endogenous opiate peptides on thyrotropin function: inhibition of thyrotropin-releasing hormone release and absence of effect on thyrotropin release.

Thyrotropin-releasing hormone (TRH) or thyroid-stimulating hormone (TSH) was measured by radioimmunoassay in the incubation medium of rat hypothalami or anterior pituitary halves, respectively. We studied the effect of opioid peptide addition (10(-8) to 10(-6) M) on TRH or TSH release. alpha- or beta-Endorphin decreased TRH release in a dose-dependent manner while only 10(-6) M Leu- or Met-enkephalin decreased TRH release. These inhibitory effects were prevented by addition of naloxone (10(-5) M). In the dose range used none of the opioid peptides modified TSH release. These results indicate that opioid peptides may play a role in the regulation of thyrotropin secretion via a hypothalamic action on TRH release.

Animals↗
PubMed1992

Binding of thyrotropin to lentil lectin is unchanged by thyrotropin-releasing hormone administration in three patients with thyrotropin-producing pituitary adenomas.

Glycoproteins have increased affinity for lentil lectin when fucose residues are bound to N-acetylglucosamine in the "core region" of their asparagine-linked oligosaccharides. In three patients with thyrotropin (TSH)-producing pituitary tumors, the proportion of serum TSH isoforms that bound to lentil (70.8% +/- 15%) was higher than that seen for TSH from normal persons (32.5 +/- 8%). Unlike normal subjects, the concentration of TSH circulating in the tumor patients after acute administration of TSH-releasing hormone (TRH) did not rise, and the TSH did not exhibit increased binding to lentil compared to basal TSH. The TSH binding to lentil in one tumor patient decreased after metoclopramide, but TSH binding to lentil generally remained unchanged after metoclopramide or L-dopa administration. We conclude that human thyrotropic tumor tissue, unlike normal thyrotrophs, generally fails to release more highly fucosylated isoforms of TSH after pharmacologic stimulation, perhaps because the tumor tissue is less readily modulated by endocrine stimuli, or because the TSH is already relatively highly fucosylated.

Adenoma↗
PubMed1989

Three distinct thyrotropin-releasing hormone-immunoreactive axonal systems project in the median eminence-pituitary complex of the frog Rana ridibunda. Immunocytochemical evidence for co-localization of thyrotropin-releasing hormone and mesotocin in fibers innervating pars intermedia cells.

The localization of thyrotropin-releasing hormone-immunoreactive structures was investigated in the hypothalamo-hypophyseal complex of the frog, Rana ridibunda, by light and electron microscopy using the conventional indirect immunoperoxidase technique and the immuno-gold technique, respectively. The localization of mesotocin-, vasotocin- and neurophysin-immunoreactive elements was compared to that of thyrotropin-releasing hormone either by comparing homologous fields on serial sections or by staining the same section with two different antibodies. Thyrotropin-releasing hormone-immunoreactive perikarya occurred mainly in the anterobasal periventricular area and dorsal extension of the preoptic nucleus, and in the lateral zone of the infundibular nucleus. In the anterobasal preoptic nucleus, the distribution of thyrotropin-releasing hormone-immunoreactive perikarya partially overlapped that of vasotocin- and mesotocin-containing neurons; however, co-localization of thyrotropin-releasing hormone with either nonapeptide could not be detected there. In contrast, in the caudal extension of the preoptic nucleus, thyrotropin-releasing hormone- and mesotocin-like immunoreactivities were frequently co-localized in the same neurons. In the external zone of the median eminence, abundant networks of thyrotropin-releasing hormone- and vasotocin-immunoreactive nerve fibers were found in the vicinity of portal capillaries, while mesotocin-immunoreactive axons were only found in the internal zone. Using the immuno-gold technique at the electron microscopic level, three distinct thyrotropin-releasing hormone-immunoreactive systems were identified in the median eminence-neurointermediate lobe complex. (1) In the external zone of the median eminence, a conspicuous population of pericapillary endings contained 100-nm dense core vesicles immunoreactive solely for thyrotropin-releasing hormone. (2) In the neural lobe of the pituitary, thyrotropin-releasing hormone immunoreactivity occurred on secretory vesicles in a subpopulation of the mesotocinergic axons containing 160-nm secretory granules; co-localization with vasotocin was never seen. (3) In the intermediate lobe, thyrotropin-releasing hormone- and mesotocin (or neurophysin I)-immunoreactivities were systematically found in the same 120-nm dense core vesicles; these thyrotropin-releasing hormone-/mesotocin-immunoreactive axon terminals frequently made synaptic contacts with melanotropic cells. The possible modulatory effect of mesotocin on thyrotropin-releasing hormone-induced alpha-melanocyte-stimulating hormone secretion was investigated using perifused frog neurointermediate lobes. Administration of graded doses of mesotocin (from 10(-10) to 10(-5) M) did not affect the spontaneous release of alpha-melanocyte-stimulating hormone. In addition, mesotocin (10(-7) and 10(-6) M) did not modify thyrotropin-releasing hormone-evoked alpha-melanocyte-stimulating hormone release.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1982

Seasonal variation of serum thyrotropin concentration and thyrotropin response to thyrotropin-releasing hormone in patients with primary hypothyroidism on constant replacement dosage of thyroxine.

Ten patients with primary hypothyroidism (aged 32--66 yr), replaced on constant daily doses of L-T4 (mean +/- SD, 1.90 +/- 0.22 micrograms/kg BW), were used to examine seasonal variations in serum levels of thyroid-related hormones for a period of 14 months. Basal and peak TSH concentrations after TRH (500 micrograms) were higher in winter than in summer. Summer values for basal TSH were all normal (normal range, less than 4.8 microU/ml), while winter values were supranormal in 5 of 10 patients. Summer values for peak TSH were subnormal or normal (normal range, 5.0--40.0 microU/ml), while winter values were supranormal in 3 patients, with the remaining values being normal [log basal TSH, 0.511 +/- 0.438 vs. 0.084 +/- 0.244 (P less than 0.05); log peak TSH, 1.394 +/- 0.410 vs. 1.017 +/- 0.423 (P less than 0.05)]. Serum resin T3 uptake, T4, free T4 index(FT4I), T3, free T3 index, and rT3 levels did not vary seasonally, although T4 and FT4I tended to fall in the winter. The summer and winter QKd interval (the interval from the onset of a QRS complex in the electrocardiogram to the appearance of the Korotkoff sound at diastolic pressure), basal metabolic rate, and serum cholesterol concentrations were all within the normal range. Basal and peak TSH after TRH were inversely correlated with serum T4 and FT4I levels. The basal TSH concentration was further inversely correlated with the seasonally altering ambient temperature. These results indicate that during the treatment of primary hypothyroidism with constant doses of T4, 1) serum TSH and its response to TRH show seasonal variation, 2) the hypersecretion TSH in the winter is related to small changes in serum T4 and FT4I levels, and 3) the seasonal variation in the serum TSH concentration may need to be taken into consideration when evaluating the adequacy of a T4 replacement dose.

Adult↗