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PubMed1990

Screening of geriatric patients for thyroid dysfunction with thyrotropin-releasing-hormone test, sensitive thyrotropin and free thyroxine estimation.

Hospitalized geriatric patients (N = 354) from an iodine-deficient area were screened with sensitive thyrotropin (TSH), free and total thyroxine (FT4, T4) and total triiodothyronine (T3) to determine the occurrence rate of clinical and subclinical thyroid dysfunction. The diagnostic value of the tests was compared to each other and to that of the thyrotropin-releasing-hormone test (TRH-test) in order to find the optimal first line screening test in geriatric patients. Clinical hyperthyroidism was found in 13, subclinical hyperthyroidism in 10, overt hypothyroidism in 6 and subclinical hypothyroidism in 8 cases. 20.6% of the patients were euthyroid but had subnormal TSH response to TRH, as a sign of possible thyroid autonomy. The low occurrence rate of clinical thyroid disorders (4.8%) does not justify the screening of geriatric patients in general, but the high probability of thyroid autonomy makes reasonable the investigation of every geriatric patient before iodine administration. Suppressed basal TSH and high FT4 were found to be both sensitive and specific in diagnosing clinical hyperthyroidism, but the predictive value was insufficient; elevated T4 and T3 are specific, but not sensitive. Basal TSH is sensitive, specific and has a good predictive value in diagnosing euthyroidism, whereas normal T4, FT4 or T3 are not specific enough for euthyroidism. Basal TSH is better as a first line test of thyroid function than FT4. A normal basal TSH confirms euthyroidism by itself. Other tests (TRH test, T4, FT4, T3) are necessary to elucidate the clinical importance of a subnormal or suppressed basal TSH.

Aged↗
PubMed1999

Effects of orexin A on thyrotropin-releasing hormone and thyrotropin secretion in rats.

Effects of orexin A on secretion of thyrotropin-releasing hormone (TRH) and thyrotropin (TSH) in rats were studied. Orexin A (50 microg/kg) was injected iv, and the rats were serially decapitated. The effects of orexin A on TRH release from the rat hypothalamus in vitro and on TSH release from the anterior pituitary in vitro were also investigated. TRH and thyroid hormone were measured by individual radioimmunoassays. TSH was determined by the enzyme-immunoassay method. The hypothalamic TRH contents increased significantly after orexin A injection, whereas its plasma concentrations tended to decrease, but not significantly. The plasma TSH levels decreased significantly in a dose-related manner with a nadir at 15 min after injection. The plasma thyroid hormone levels showed no changes. TRH release from the rat hypothalamus in vitro was inhibited significantly in a dose-related manner with the addition of orexin A. TSH release from the anterior pituitary in vitro was not affected with the addition of orexin A. The findings suggest that orexin A acts on the hypothalamus to inhibit TRH release.

Animals↗
PubMed1995

The functional significance of the second extracellular loop of thyrotropin receptor in thyrotropin- and thyroid stimulating antibody-dependent signal transduction.

In order to determine the functional significance of the extracellular loop of human thyrotropin receptor (hTSHR), two peptides composed of eight amino acids were inserted into hTSHR by ligating synthetic oligonucleotides into +1811 NCol site of hTSHR cDNA. Mutant hTSHR cDNAs which encode a hydrophobic peptide (ATVLVVPM) and a hydrophilic peptide (GTTRTVAM) between +572 Met and +573 Asp were transfected into Chinese hamster ovary (CHO) cells to develop F-cell lines and R-cell lines, respectively. Of the resulting cloned cell lines, F-29 and R-9 were shown to express mutant hTSHs at the protein level by Western blotting and at the mRNA level by reverse transcription-polymerase chain reaction (RT-PCR). We show that neither thyrotropin (TSH) nor IgGs from patients with Graves' disease stimulated cAMP production by F-29 and R-9 cells. 125I-TSH binding study revealed that F-29 and R-9 cells do not bind TSH. Our data demonstrate that the mutations impaired TSH-binding and incapacitated the cells from responding to TSH. The evidence suggests that the second extracellular loop of hTSHR has an important role in TSH and thyroid stimulating antibody (TSAb)-dependent signal transduction.

Amino Acid Sequence↗
PubMed1990

Cloning, chromosomal assignment, and regulation of the rat thyrotropin receptor: expression of the gene is regulated by thyrotropin, agents that increase cAMP levels, and thyroid autoantibodies.

A rat thyrotropin (thyroid-stimulating hormone, TSH) receptor cDNA was isolated that encoded a protein of 764 amino acids, Mr 86,528. Transfection of the cDNA caused COS-7 cells to develop a TSH-sensitive adenylate cyclase response and the ability to bind 125I-labeled TSH; both activities were similar to those of rat FRTL-5 thyroid cells and not duplicated by lutropin. The gene represented by the cDNA was assigned to mouse chromosome 12 and human chromosome 14. Northern analyses identified two species of mRNA, 5.6 and 3.3 kilobases, in FRTL-5 thyroid cells; the transcripts appeared to differ only in the extent of their 3' noncoding sequences. There were minimal amounts of the two mRNAs in rat ovary, and neither was detected in RNA preparations from rat testis, liver, lung, brain, spleen, and FRT thyroid cells, which do not have a functional TSH receptor. TSH decreased both mRNA species 3- to 4-fold within 8 hr in FRTL-5 thyroid cells; down-regulation was dependent on TSH concentration and duplicated by forskolin, cholera toxin, or 8-bromo-cAMP but not by a phorbol ester. Down-regulation was also duplicated by thyroid-stimulating autoantibodies, which increased cAMP levels, but not by thyrotropin binding-inhibiting auto-antibodies, which actually increased TSH receptor mRNA levels.

Amino Acid Sequence↗
PubMed1991

Thyrotropin-luteinizing hormone/chorionic gonadotropin receptor extracellular domain chimeras as probes for thyrotropin receptor function.

To define the sites in the extracellular domain of the human thyrotropin (TSH) receptor that are involved in TSH binding and signal transduction we constructed chimeric thyrotropin-luteinizing hormone/chorionic gonadotropin (TSH-LH/CG) receptors. The extracellular domain of the human TSH receptor was divided into five regions that were replaced, either singly or in various combinations, with homologous regions of the rat LH/CG receptor. The chimeric receptors were stably expressed in Chinese hamster ovary cells. The data obtained suggest that the carboxyl region of the extracellular domain (amino acid residues 261-418) and particularly the middle region (residues 171-260) play a role in signal transduction. The possibility is also raised of an interaction between the amino and carboxyl regions of the extracellular domain in the process of signal transduction. With respect to hormone binding, substitution of the entire extracellular domain of the LH/CG receptor for the corresponding region of the TSH receptor resulted in high-affinity human CG binding with complete loss of TSH binding. Surprisingly, however, there was at least one chimera with a substitution at each of the five domains that still retained high-affinity TSH binding. Substitution of residues 1-170 of the TSH receptor with the corresponding region of the LH/CG receptor was associated with the retention of high-affinity TSH binding but ligand specificity was lost in that TSH and human CG could interact functionally with the receptor. In summary, these studies suggest that the middle region and carboxyl half of the extracellular domain of the TSH receptor are involved in signal transduction and that the TSH-binding region is likely to span the entire extracellular domain, with multiple discontinuous contact sites.

Animals↗
PubMed2000

cAMP response element-binding protein-binding protein mediates thyrotropin-releasing hormone signaling on thyrotropin subunit genes.

Transcription of pituitary alpha-glycoprotein hormone subunit (alpha-GSU) and thyrotropin beta subunit (TSH-beta) genes is stimulated by thyrotropin-releasing hormone (TRH). Since cAMP response element-binding protein (CREB)-binding protein (CBP) integrates a number of cell signaling pathways, we investigated whether CBP is important for TRH stimulation of the TSH subunit genes. Cotransfection of E1A in GH(3) cells completely blocked TRH stimulation of the TSH subunit genes, suggesting that CBP is a key factor for TRH signaling in the pituitary. CBP and Pit-1 acted synergistically in TRH stimulation of the TSH-beta promoter, and amino acids 1-450 of CBP were sufficient for the TRH effect. In contrast, on the human alpha-GSU promoter, CREB and P-Lim mediated TRH signaling. Intriguingly, CREB was phosphorylated upon TRH stimulation, leading to CBP recruitment to the alpha-GSU promoter. CBP also interacted with P-Lim in a TRH-dependent manner, suggesting that P-Lim is an important factor for non-cAMP response element-mediated TRH stimulation of this promoter. Distinct domains of CBP were required for TRH signaling by CREB and P-Lim on the alpha-GSU promoter, amino acids 450-700 and 1-450, respectively. Thus, the amino terminus of CBP plays a critical role in TRH signaling in the anterior pituitary via both Pit-1-dependent and -independent pathways, yielding differential regulation of pituitary gene products.

CREB-Binding Protein↗
PubMed2001

Reactivity of thyrotropin receptor autoantibodies with the thyrotropin receptor on western blots.

Affinity purified recombinant human thyrotropin receptor (TSHR) was run on sodium dodecyl sulfate (SDS) gels and subjected to a renaturing and blotting procedure. Twenty sera from thyrotropin receptor autoantibodies (TRAb)-positive patients with a history of hyperthyroidism and 20 sera with high levels of TSH blocking activity were analyzed. Four of 20 sera with blocking-type of TRAb (i.e., TSH antagonist activity) were able to recognize the mature, fully glycosylated 120-kd form of the receptor on blots of gels run under reducing conditions. No sera recognized the 100-kd high mannose precursor form of the TSHR. Three of the four recognized a 74-kd band and 2 of the 4 recognized a 50-kd band. These bands are probably proteolytic cleavage fragments of the mature 120-kd TSHR. In the absence of reducing agent the same 4 of 20 sera described above together with a further serum sample (i.e., 5/20 in total) reacted with the 120-kd form of the receptor. No specific reaction with the TSHR was observed on Western blots with the remaining 15 sera with TSH blocking activity, nor with 20 sera from patients with a history of hyperthyroidism, nor with sera from 10 healthy blood donors, 10 Hashimoto sera (negative for TRAb) and 10 systemic lupus erythematosus sera. No clear differences were observed in the TRAb positive sera that were reactive and nonreactive on Western blots in terms of their ability to inhibit TSH binding or to immunoprecipitate 125I-labeled TSHR. Overall, our results indicate that the mature 120-kd form of the TSHR that is principally responsible for binding TSH is also responsible for binding TRAb (when this binding can be detected). These observations together with immunoprecipitation and TSH binding inhibition studies, emphasize the close relationship between the receptor's binding sites for TSH and TRAb.

Antibody Specificity↗
PubMed1998

Thyrotropin receptor expression in cultured Graves' orbital preadipocyte fibroblasts is stimulated by thyrotropin.

Our laboratory has shown recently that the thyrotropin receptor (TSHr) is expressed in orbital adipose/connective tissues from patients with Graves' ophthalmopathy (GO), and that this receptor is not demonstrable in orbital tissues from normal individuals. In order to study the regulation of TSHr expression in the orbit in GO, we treated cultures of Graves' orbital preadipocyte fibroblasts with the TSHr ligand thyrotropin (TSH; 100 mU/L). We found increased expression of both intact (2.4 kb) and variant (1.3 kb) TSHr mRNA and of TSHr protein in orbital fibroblasts following 72 hr treatment with TSH. These studies suggest that the expression of this receptor in the orbit in vivo may be stimulated by TSH or other TSHr ligands, and that this stimulation may be important in the development of GO.

Adipocytes↗
PubMed1998

Hypothalamic thyrotropin-releasing hormone and thyrotropin biological activity.

Hypothalamic thyrotropin-releasing hormone (TRH) is the main positive regulator of thyrotropin (TSH) secretion. TRH action and the negative feedback of thyroid hormone are integrated in order to guarantee appropriate thyroid stimulation. TRH action affects various steps of the biosynthetic process within thyrotrophs, with major effects on the posttranslational maturation of TSH oligosaccharide chains, and is necessary for the secretion of the glycoprotein hormone with full biological activity. Since the first description in 1979 of some patients with central hypothyroidism of hypothalamic origin associated with the secretion of TSH molecules with conserved immunoreactivity but decreased bioactivity, a large body of evidence has accumulated in more recent years showing that changes of the oligosaccharide chains have a great impact on the biological properties of circulating TSH and occur in various in vivo situations. These findings have lead to the new concept of a qualitative regulation of TSH secretion. This can be achieved mainly through the transcriptional and posttranscriptional regulation of the complex enzymatic machinery devoted to the processing of the three oligosaccharide chains linked to specific asparagine residues of TSH heterodimer. Data obtained in several physiological and pathological conditions, which are characterized by an increased or diminished TRH action, indicate that both qualitative and quantitative regulations cooperate within thyrotrophs in order to adjust thyroid-stimulating activity to the temporary needs.

Adenoma↗
PubMed1991

Thyrotropin response to thyrotropin-releasing hormone in elderly patients with and without acute illness.

The response of thyrotropin (TSH) to thyrotropin-releasing hormone (TRH) was measured in 70 clinically euthyroid elderly patients who were acutely ill and in 70 age- and sex-matched euthyroid controls who were free of acute disease. The incremental TSH response (delta TSH) was often blunted (less than 2 mU/l) in both groups, though more often in those with acute illness (30%) than in those without (19%). However, in patients from both groups who had a blunted delta TSH, there was often a substantial proportional rise in TSH. A substantial proportional TSH rise may be useful in differentiating between genuine thyroid disease and euthyroid sick syndrome in elderly patients with a blunted delta TSH.

Acute Disease↗
PubMed1981

Serum prolactin and thyrotropin responses to thyrotropin-releasing hormone in men with alcoholic cirrhosis.

The serum concentrations of prolactin (PRL) and thyrotropin (TSH) in 12 males with alcoholic cirrhosis during basal condition and after stimulation with thyrotropin-releasing hormone (TRH) were compared with the concentrations in ten thiazide-treated hypertensive and nine normal men. The basal as well as the TRH-stimulated increase in serum PRL was significantly elevated in the cirrhotic males, while the increase in serum TSH was unchanged, compared with hypertensive and normal men. No correlation between clinical or laboratory parameters and serum PRL was found. Serum estradiol was equal in cirrhotic and control subjects and no correlation was found between serum PRL and serum estradiol. These findings favour the concept that raised serum PRL in cirrhotic patients might be caused by a diminished dopaminergic neurotransmission.

Adult↗
PubMed1975

The response of thyrotropin and triiodothyronine to various doses of thyrotropin releasing hormone in normal man.

The relationship between serum thyrotropin (TSH) and serum triiodothyronine (T3) before and after injection of different doses of thyrotropin releasing hormone (TRH), given as single injections or as multiple injections with short intervals, was investigated in normal men. A positive correlation between prestimulated serum TSH and serum T3 levels and between the increase in the serum TSH and the serum T3 levels after TRH was found when repeated tests were performed in the same individual. There was a dose dependent TSH and T3 response to TRH. The smallest dose that produced a maximal response of both TSH and T3 was only 30 mug TRH. After six injections of 30 mug TRH with an interval of 30 minutes the increase in TSH was two times and the increase in T3 was three times as high as the maximal increase after single injections of TRH. This test with multiple injections of TRH may prove to be of clinical value in the measurement of both pituitary and thyroid function in selected patients. The close positive correlation between the serum TSH and serum T3 levels in basal conditions, demonstrated in four normal subjects in this study, probably reflects the steady state level determined by the hypothalamus from which the feedback control of TSH secretion operates.

Adult↗
PubMed1992

Evidence for normal feedback inhibition of triiodothyronine on the thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) in abstinent male alcoholics.

Disturbances in the hypothalamic-pituitary-thyroid (HPT) axis have been reported in abstinent, noncirrhotic alcoholics, including a reduction in thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) and reductions in triiodothyronine (T3). Some evidence has suggested that a portion of alcoholics may also exhibit a disturbance in the feedback inhibition of thyroid hormone on TSH release. To evaluate the function of the HPT axis negative feedback system in abstinent, noncirrhotic alcoholic men we compared the TSH response with TRH before and after a standard suppressive dose of T3. Ten alcoholic subjects were studied and compared with four control subjects from a previous study and to literature values. The mean percent reduction in TSH response in the alcoholic subjects of 74 +/- 7% was almost identical to the 71 +/- 9% reduction observed in normal subjects. The present findings indicate that noncirrhotic, abstinent alcoholic men exhibit normal suppression of the TSH response to TRH following T3.

Adult↗
PubMed1987

The thyrotropin response to thyrotropin-releasing hormone as a biological marker of suicidal risk in depressive patients.

In order to evaluate a possible predictive value for committing suicide of a reduced thyrotropin-stimulating hormone (TSH) response to thyrotropin-releasing hormone (TRH) stimulation we studied 306 depressed patients. The patients were followed for a mean of 5.8 (SD 2.9) years. During this period, 18 patients committed suicide. The TSH response to TRH stimulation in these 18 patients who committed suicide was lower than in the patients who did not commit suicide. The difference is not statistically significant. It is concluded that the TSH response to TRH cannot be said to identify the patients who later commit suicide.

Adjustment Disorders↗
PubMed1992

The thyrotropin response to thyrotropin-releasing hormone as a predictor of response to treatment in depressed outpatients.

We evaluated the predictive value of the thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH) in 32 depressed outpatients completing a double-blind placebo-controlled trial of s-adenosyl-l-methionine (SAMe), which failed to show any significant difference between SAMe and placebo. Treatment response was defined as the change in Hamilton Rating Scale for Depression (HRSD-24) score between baseline and the end of the six-week trial. Subjects with TSH response outside the normal range (7-25 uU/ml) had a significantly greater response than patients with a normal response. There was also a significant correlation between absolute deviations from the mean TSH response (16 uU/ml) and changes in HRSD-24 scores.

Adolescent↗
PubMed1976

Thyrotropin response to thyrotropin-releasing hormone in fullterm, euthyroid and hypothyroid newborns.

The serum concentration of thyrotropin (TSH) and the TSH response following thyrotropin-releasing hormone (TRH) were studied in 16 euthyroid babies from 16 to 172 hours after birth and in 2 primary hypothyroid babies, 3 and 28 days of age. Serum-TSH was measured before an intravenous injection of 40 mug TRH and after 30 and 180 min. In the euthyroid babies increased basal levels of TSH were seen shortly after birth, followed by a pronounced decline. The extent of TSH increase after TRH could be correlated with the basal levels, and the relative increase was comparable to that which occurs in adults. In the hypothyroid babies very high basal levels of serum-TSH were seen, 125 and 400 muU/ml respectively, with no further increase following TRH stimulation. It was concluded that in euthyroid fullterm newborn, the relative response of serum-TSH to TRH was equal to that of adults, in spite of elevated thyroid hormone concentrations. In the hypothyroid newborn very high levels of serum-TSH were seen and a supplementary TRH-test seems without diagnostic value in congenital hypothyroidism.

Congenital Hypothyroidism↗
PubMed1989

Thyrotropin and prolactin responses to different doses of thyrotropin-releasing hormone in depression.

The effects of low doses of thyrotropin-releasing hormone (TRH, 50 and 200 micrograms) on thyrotropin (TSH) and prolactin levels have been studied in depressed women and compared with the depressive condition and with the results of the dexamethasone suppression test (DST). TRH administration elicited blunted hormonal responses that were not correlated either with the age of the patients or with DST results. Different effects were observed in subgroups of depressive patients classified according to DSM III and ICD. No correlation was found between hormone responses and the scores of Hamilton Rating Scale and Montgomery Depression Scale. The effects of 50 micrograms on TSH were significant and inversely correlated with Anxiety Rating Scale scores. No dose-response effect was apparent of prolactin and TSH in depressed patients, suggesting an impaired function of pituitary TRH receptors.

Adult↗
PubMed1978

Thyrotropin and prolactin secretory patterns during 24-hours infusion of thyrotropin-releasing hormone in calves.

Plasma levels of thyrotropin (TSH), prolactin (Prl), growth hormone (GH), thyroxine (T4), and triiodothyronine (T3) were measured in response to continuous 24-h infusion of synthetic thyrotropin-releasing hormone (TRH) in normal and surgically thyroidectomized (THYX) calves in a series of 2 experiments. In the 1st experiment, the low dose of TRH (0.077 microgram/min) had no effect on any hormone levels measured. Plasma TSH concentration increased significantly (p less than 0.05) in response to TRH infusion (0.77 microgram/min) in both experiments, but plasma TSH levels plateaued and then declined in both cases despite continued TRH infusion and irrespective of the presence or absence of a thyroid gland. A similar pattern of secretion, though less markedly decreased over time, was observed for plasma Prl in both experiments. The higher dose (0.77 microgram/min) of TRH had no effect on plasma GH concentration in the 1st infusion, but did result in a significant (p less than 0.05) increase in overall mean concentration of GH in both normal and THYX calves in the 2nd experiment. Removal of the thyroid gland, thus removing the source of increasing T4 and T3 levels seen in normal calves infused with TRH, failed to alter the secretory patterns of TSH and Prl. These data suggest that feedback inhibition by increasing plasma thyroid hormone concentrations was not responsible for the failure of TSH and, to a lesser extent, Prl to maintain chronically elevated plasma levels in response to continuous 24-h TRH infusion. It is suggested that a depletion of pituitary TSH and Prl stores readily secretable in response to a constant dosage level of TRH may be responsible for the secretory patterns observed.

Animals↗