• YAKHAK HOEJI
• /
• v.51 no.6
• /
• pp.490-494
• /
• 2007

TRH (thyrotropin-releasing hormone) was chemically synthesized utilizing solution phase peptide chemistry for the process development of large scaled synthesis. All the synthetic steps performed in relatively mild conditions, higher yields, easier preparations, minimum racemizations, and separation and purification by recrystallizations.

• Journal of Pharmaceutical Investigation
• /
• v.27 no.2
• /
• pp.99-108
• /
• 1997

To evaluate the feasibility of mucosal delivery of thyrotropin releasing hormone (TRH) through various mucosae, enzymatic degradation and stabilization of TRH in the nasal, rectal and duodenal extracts of rabbits were studied. TRH in the extracts was assayed by HPLC and its degradation was found to follow apparent first-order kinetics. The residual concentrations of TRH in the mucosal extracts of nasal, rectal and duodenal segments after 24 hr of incubation were found to be $65.1({\pm}1.1),\;19.7({\pm}2.7)$ and 0%, and in the serosal extracts, $65.6({\pm}5.5),\;75.2({\pm}1.1)$ and $68.7({\pm}1.4)%$, respectively. This result suggests that there is a significant difference in the activity of TRH-degrading enzymes among the sites of administration. The inhibition of TRH degradation in the mucosa extracts was kinetically investigated using various additives such as thimerosal, benzalkonium chloride, disodium edetate, ${\sigma}-phenanthroline$, dithiothreitol and dithioerythritol, and $IC_{50}$ values of inhibitors were calculated. The results obtained showed that thimerosal (0.5 mM) and benzalkonium chloride (0.141 mM) protected TRH from the enzymatic degradation in all the mucosa extracts more than 95% after 24 hr of incubation.

• Biomolecules & Therapeutics
• /
• v.7 no.3
• /
• pp.263-270
• /
• 1999

The in vitro permeation of thyrotropin-releasing hormone (TRH) through rabbit nasal, rectal and duodenal mucosae was studied in the absence and presence of an enzyme inhibitor and permeation enhancer. TRH in the donor and receptor solutions was assayed by HPLC. When thimerosal (TM, 0.5 mM) was added to the donor cell as an inhibitor, the permeation rate of TRH (200 $\mu\textrm{g}$/ml) increased linearly as a function of time. Fluxes of TRH through the nasal, rectal and duodenal mucosae were found to be 33.3$\pm$5.9, 11.8$\pm$1.9 and 9.6$\pm$0.7 $\mu\textrm{g}$/$\textrm{Cm}^2$/hr, respectively. The addition of sodium glycocholate, glycyrrhizic acid ammonium salt, sodium taurodihydrofusidate or L-$\alpha$-lysophosphatidylcholine to the donor solution containing TM did not result in the significant increase of permeation flux except for the duodenal mucosa, comparing with that in the presence of TM alone. Consequently, it was suggested that the nasal route was advantageous for systemic delivery of TRH, and the addition of TM and/or an enhancer was necessary to maximize the transmucosal permeation of TRH.

• The Korean Journal of Nuclear Medicine
• /
• v.24 no.1
• /
• pp.93-100
• /
• 1990

To evaluate the utility of autoradiographic technique in the detection of TRH receptor changes in brain after the various kinds of stimulation or drug administration, we tried the characterization of TRH receptor in mouse brain and autoradiography in rat brain as a preliminary study. The Kd value of [3-H] MeTRH to TRH receptors of adult male ICR mouse brain (cebellum and spinal cord were excluded) was 3.55+0.6 nM and Bmax was 3.44+0.52 fmol/mg wet tissue by saturation analysis. The Kd value of TRH to TRH receptors was 133.8+28.2 nM by competition analysis. And we could visualize the distribution of TRH receptors in rat brain by autoradiographic technique.

• The Korean Journal of Physiology and Pharmacology
• /
• v.2 no.1
• /
• pp.101-108
• /
• 1998

We investigated the effect of ${\alpha}-subunit$ of the stimulatory GTP-binding protein ($G{\alpha}_s$) gene mutation on the expression of the thyrotropin-releasing hormone (TRH) receptor (TRH-R) gene in GH3 cells and in growth hormone (GH)-secreting adenomas of acromegalic patients. In the presence of cyclohexicmide, forskolin and isobutylmethylxanthine, cholera toxin, and GH-releasing hormone (GHRH) decreased rat TRH-R (rTRH-R) gene expression by about 39%, 43.7%, and 46.7%, respectively. Transient expression of a vector expressing mutant-type $G{\alpha}_s$ decreased the rTRH-R gene expression by about 50% at 24 h of transfection, whereas a wild-type $G{\alpha}_s$ expression vector did not. The transcript of human TRH-R (hTRH-R) gene was detected in 6 of 8 (75%) tumors. Three of them (50%) showed the paradoxical GH response to TRH and the other three patients did not show the response. The relative expression of hTRH-R mRNA in the tumors from patients with the paradoxical response of GH to TRH did not differ from that in the tumors from patients without the paradoxical response. Direct PCR sequencing of $G{\alpha}_s$ gene disclosed a mutant allele and a normal allele only at codon 201 in 4 of 8 tumors. The paradoxical response to TRH was observed in 2 of 4 patients without the mutation, and 2 of 4 patients with the mutation. The hTRH-R gene expression of pituitaty adenomsa did not differ between the tumors without the mutation and those with mutation. The present study suggests that the expression of TRH-R gene is not likely to be a main determinant for the paradoxical response of GH to TRH, and that $G{\alpha}_s$ mutation may suppress the gene expression of TRH-R in GH-secreting adenoma. However, a certain predisposing factor(s) may play an important role in determining the expression of TRH-R.

• Clinical and Experimental Pediatrics
• /
• v.50 no.6
• /
• pp.576-579
• /
• 2007

The syndrome of resistance to thyroid hormone (RTH) is characterized by reduced tissue sensitivity to thyroid hormone (TH). In the majority of subjects, RTH is caused by mutations in the thyroid hormone receptor beta ($TR{\beta}$) gene, located on the chromosome locus 3p24.3. RTH is inherited in an autosomal dominant manner. The clinical presentation of RTH is variable, but common features include elevated serum levels of thyroid hormone (TH), a normal or slightly increased thyrotropin (thyroid stimulating hormone, TSH) level that responds to thyrotropin releasing hormone (TRH), and goiter. We report a 4 year-old girl, who was clinically euthyroid in spite of high total and free $T_4$, and $T_3$ concentrations, while TSH was slightly increased. Sequence analysis of the thyroid hormone receptor beta gene (THRB) confirmed a heterozygous C to T change at nucleotide number 1303, resulting in a substitution of histidine by tyrosine at codon 435 (H435Y). Further analysis of her parents revealed that the H435Y variation was a de novo mutation since neither parents had the variation. Her parents' TH and TSH levels were within normal range.

• Asian-Australasian Journal of Animal Sciences
• /
• v.23 no.12
• /
• pp.1668-1676
• /
• 2010

The somatotropic axis plays a key role in proliferation and differentiation of avian organs during both pre- and posthatching periods. This review discusses the complexity of regulation of the endocrine system for chicken development and growth by growth hormone (GH), insulin-like growth factor (IGF), and IGF binding protein (IGFBP). In addition, the thyrotropic axis, including thyrotropin-releasing hormone (TRH) and thyroid hormones ($T_4$ and $T_3$), is also involved in the GH-secreting pattern. In mammals, IGFI and -II are always sequestered in a 150 kDa non-covalent ternary complex. This complex consists of one molecule each of IGF-I or IGF-II, IGFBP-3 or IGFBP-5 and an acid labile subunit (ALS). Chick ALS is identified in different strains for the first time, and further investigation of the expression of ALS on developmental stage and ALS effect on IGF bioavailability may be addressed in the future.

• The Korean Journal of Nuclear Medicine
• /
• v.14 no.1
• /
• pp.1-8
• /
• 1980

Serum TSH levels were measured by radioimmunoassay before and after intravenous administration of synthetic thyrotropin-releasing hormone (TRH) to 15 normal subjects and 55 patients with primary thyroid disease (14 patients with euthyroidism, 24 patients with thyrotoxicosis and 17 patients with hypothyroidism) to evaluate pituitary TSH reserve and its diagnostic availability. The observed results were as follows. 1. In normal subjects, serum TSH responses to synthetic TRH were $3.2{\pm}1.0$ at 0min (baseline TSH level), $8.0{\pm}4.0$ at 10min, $11.7{\pm}5.0$ at 20min, $13.7{\pm}7.1$ at 30min, $9.7{\pm}5.0$ at 60min., $5.2{\pm}2.0$ at 120min. and $3.6{\pm}0.4{\mu}U/ml$ at 180 min. Serum TSH peaked at $20{\sim}30$ minutes and returned nearly to baseline at 180minutes. 2. In euthyroid group, serum TSH responses to synthetic TRH were $3.3{\pm}1.6$ at 0min, $8.6{\pm}8.0$ at 10min, $10.9{\pm}8.5$ at 20min, $12.5{\pm}8.4$ at 30min, $9.0{\pm}5.9$ at 60min, $5.6{\pm}2.6$ at 120min and $3.5{\pm}1.3{\mu}U/ml$ at 180min. No significant difference revealed between euthyroid group and normal subjects (p>0.05). 3. In hyperthyroid group, serum TSH responses to synthetic TRH were $1.5{\pm}0.6$ at 0min, $2.2{\pm}0.8$ at 10min., $2.3{\pm}1.0$ at 20min., $2.4{\pm}1.5$ at 30min., $2.1{\pm}1.1$ at 60min., $1.9{\pm}0.2$ at 120min. and $1.5{\pm}0.8{\mu}U/ml$ at 180min., No response to TRH showed. 4. In hypothyroid group, mean values of serum TSH response to synthetic TRH were 42.0 at 0min., 60.6 at 10min., 124.8 at 20min., 123.0 at 30min., 101.6 at 60min., 64.3 at 120min. and $15.5{\mu}U/ml$ at 180 min., Patients with primary hypothyroidism showed an exaggerated TSH response to synthetic TRH despite their high basal TSH. 5. Side effects attending synthetic TRH administration were transient nausea (59.0%), desire to micturate (59.0%), feeling of flushing(19.7%), dizziness (45.9%), metallic taste (9.8%) and headache (19.7%). Any side effect didn't show in 16.4%. These symptoms began almost immediately after TRH intravenous injection and lasted several minutes, and not related to dose or response in the person experiencing it.

• Biomolecules & Therapeutics
• /
• v.26 no.5
• /
• pp.512-519
• /
• 2018

Phthalates widely used in the manufacture of plastics have deeply penetrated into our everyday lives. Recently, a concern over the toxicity of phthalates on thyroid, has been raised but in most of cases, the doses employed were unrealistically high. To investigate the effects of phthalates on thyroid, we investigated the effects of the repeated oral exposure to low to high doses (0.3, 3, 30 and 150 mg/kg) di-2-ethylhexylphthalate (DEHP) from weaning to maturity for 90 days in juvenile rats on the thyroid. The histological examination revealed that DEHP significantly induced hyperplasia in the thyroid from the doses of 30 mg/kg, which was confirmed with Ki67 staining. In line with this finding, increased mRNA expression of thyrotropin releasing hormone (Trh) was observed in the thyroid of female at 0.3 mg/kg and 150 mg/kg as determined by RNAseq analysis. Moreover, significantly increased expression of parathyroid hormone (Pth) in the female at 0.3 mg/kg, and thyroglobulin (Tg) and thyroid hormone responsive (Thrsp) in the male at 0.3 mg/kg were noted in the blood, of which changes were substantially attenuated at 150 m/kg, alluding the meaningful effects of low dose DEHP on the thyroid hormone regulation. Urinary excretion of mono-2-ethylhexyl-phthalate (MEHP), a major metabolite of DEHP was determined to be 4.10 and 12.26 ppb in male, 6.65 and 324 ppb in female at 0.3 and 30 mg/kg DEHP, respectively, which fell within reported human urine levels. Collectively, these results suggest a potential adverse effects of low dose phthalates on the thyroid.

• Clinical and Experimental Pediatrics
• /
• v.52 no.9
• /
• pp.1021-1028
• /
• 2009

Purpose:Medical therapy is the initial treatment for children with Graves disease to avoid complications of other treatments. However, optimal treatment for childhood Graves disease is controversial because most patients require relatively long periods of medical therapy and relapse is common after medication discontinuation. Therefore, this study aimed to search clinical or biochemical characteristics that could be used as remission predictors in Graves disease. Methods:We retrospectively studied children diagnosed with Graves disease, treated with anti-thyroid agents, and observed for at least 3 years. Patients were categorized into remission and non-remission groups, and the groups were compared to determine the variables that were predictive of achieving remission. Results:Sixty-four patients were enrolled, of which 37 (57.8%) achieved remission and 27 (42.2%) could not achieve remission until the last visit. Normalization of thyroid-stimulating hormone-binding inhibitory immunoglobulin (TBII) after treatment was faster in the remission group than in the non-remission group (remission group, $15.5{\pm}12.07$ vs. non-remission group, $41.69{\pm}35.70$ months). Thyrotropin-releasing hormone (TRH) stimulation tests were performed in 28 patients. Only 2 (8.3%) of 26 patients who showed normal or hyper-response in TRH stimulation test relapsed. Binary logistic regression analysis identified rapid achievement of TBII normalization after treatment as a significant predictor of remission. Six percent of patients achieved remission within 3 years and 55.8% achieved it within 6 years. Conclusion:Rapid achievement of TBII normalization can be a predictor of remission in childhood Graves disease. The TRH stimulation test can be a predictor of maintenance of remission.