Endocrinology and Metabolism

Original Articles

Remission, Relapse, and Thyroid-Related Parameters Measurement at Discontinuation of Low-Dose Anti-Thyroid Drugs in Graves’ Disease: Nami Suzuki, Kosuke Inoue, Natsuko Watanabe, Jaeduk Yoshimura Noh, Ai Yoshihara, Miho Fukushita, Masako Matsumoto, Masakazu Koshibu, Rei Hirose, Tatsuya Iida, Kiminori Sugino, Koichi Ito; Received November 4, 2025 Accepted February 3, 2026 Published online May 15, 2026; DOI: https://doi.org/10.3803/EnM.2025.2771 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
This study aimed to elucidate the relationship between thyroid-related parameters and the prognosis of Graves’ disease (GD).
Methods
This retrospective cohort study included patients newly diagnosed with GD between January 2009 and December 2010. We applied multivariable Cox proportional hazard models to estimate the hazard ratio (HR) and 95% confidence intervals (CI) for the relationships between the parameters at anti-thyroid drug (ATD) discontinuation and GD relapses. We also developed prediction models for GD prognosis based on parameters at ATD initiation and discontinuation using logistic regression and machine learning algorithm (gradient-boosting machine [GBM]).
Results
The median observation period was 11.3 years. In 1,508 patients who discontinued ATDs after the first course, 1,073 remained in remission, whereas 435 relapsed within a median of 20 months (interquartile range, 10.0 to 49.7). In the Cox model, we found that patients with younger age, higher thyroid stimulating hormone (TSH) receptor antibody (TRAb), and lower TSH levels at ATD discontinuation were more likely to relapse than those without (per 5-year increase in age: HR, 0.92 [95% CI, 0.88 to 0.95]; per 1-unit increase in TSH: HR, 0.86 [95% CI, 0.79 to 0.94]; per 1-unit increase in TRAb: HR, 1.15 [95% CI, 1.06 to 1.24]). Both logistic regression and GBM demonstrated similar predictive performance (area under the curve, 0.61 to 0.63), showing that age and parameters at both ATD initiation and discontinuation contribute to GD relapse.
Conclusion
TRAb levels at ATD discontinuation may contribute to the prognosis of GD, but they are not sufficient on their own to predict relapse.

The Changes of Serum Soluble Intercellular Adhesion Molecule-1(ICAM-1) According to the Clinical Course of Graves' Disease Treated with Antithyroid Drug.: Jin Hong Lee, Jae Kyu Shin, So Young Bak, Bong Soo An, Bon Jeong Ku, Mee Ae Ahn, Jun Sik Jeon, Young Kun Kim, Heung Kyu Ro; J Korean Endocr Soc. 1996;11(3):293-301. Published online November 7, 2019

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Abstract PDF: Background
TSH binding inhibiting imunoglobulins(TBII) are autoimmune antibody causing autoimmune thyroid diseases such as Graves disease or Hashimoto's thyroiditis, while intercellular adhesion molecule-1(ICAM-1) is known as a substance expressed at the site of autoimmune reaction in relation with lymphocyte infiltration. The serum TBII activity is used as an index of the disease course and prognosis of Graves disease treated with antithyroid drugs, propylthiouracil or methimazole. The aim of this study is to understand the change of serum ICAM-1 level according to the change of the degree of autoimmunity and clinical course of Graves disease. Methods: In order to study the change of soluble ICAM-1 and relationship to the immune mechanism of Graves' disease, we measured serum levels of TBII and ICAM-1 in patients(n 35) with Graves disease before and after treatment with antithyroid drugs and in relapsed patients using a highly sensitive ELISA method. Results: The serum levels of TBII and ICAM-1 were markedly elevated in patients with Graves disease before treatment than normal controls and there were good correlation between TBII and ICAM-1 level. In patients with normalized TBII levels after 22 months antithyroid drug treatment, the ICAM-1 levels became normal but in the patients with high serum TBII level showed high serum level of ICAM-1 even with clinical remission with same treatment. The serum levels of TBII and ICAM-1 in relapsed patients were elevated as those of patients before treatment. Conclusion: With the above results, we can conclude that not only the TBII level but seru ICAM-1 level also reflect the degree of autoimmune activity of Graves disease and may be used as an index of the disease course and prognosis of Graves disease treated with antithyroid drugs.

Insulin Like Growth Factor-I and Insulin Like Growth Factor Binding Protein-3 in Human Thyroid Cystic Fluids.: In Myung Yang, Jeong Taek Woo, Sung Woon Kim, Jin Woo Kim, Young Seol Kim, Young Kil Choi, Byoung Joon Kim, Seung Joon Oh; J Korean Endocr Soc. 1995;10(4):395-404. Published online November 7, 2019

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Abstract PDF: In the thyroid tissue, thyrotrophin(TSH) and IGF-I played major role of the goitrogen. But the evidences and precise mechanism of these two factors were not known so much. Actually local secretion of thyroid IGF-I was originated from its fibroblasts mainly. We guessed major roles of IGFs in the thyroid tissue were local paracrine effect of thyroid cells proliferation and differentiation which concert with TSH. Recently, some reporters described the source of thyroid IGF-I were partly from thyroid follicular cells and its action were synergistic with TSH. We measured TSH, IGF-I and IGFBP-3 from sera and thyroid cystic fluids in 36 patients with simple thyroid cyst and examined into correlation between TSH, IGF-I and IGFBP-3.1) According to cyst/serum TSH ratio, we classified two groups(Group I; c/s TSH <1, n=19. Group II; c/s TSH >1, n=17). This classification criteria means that cystic TSH level were increased than that of serum or not.2) The serum TSH, IGF-I and IGFBP-3 levels are not difference between group I and II.3) Cystic TSH were dependent on the serum TSH in Group I, but negative correlation in Group II. In Group II, cystic TSH was significant increased.4) Serum IGF-I were positive correlation in each Group5) In Group II, cystic IGF-I was not exceed than those of serum IGF-I, but some cystic IGFBP-3 were more increased than those of serum.6) In Group II, cystic IGFBP-3 increased than serum TSH, and cystic IGFBP-3 was positive correlation with cystic TSH and cystic IGF-I.As these data suggested that cystic TSH and cystic IGF-I levels may influence cystic IGFBP-3 level. The main effect for maintenance of cyst was mediated by cystic TSH and cystic IGFBP-3. But the cystic IGFBP-3 has major role for thyroid cyst than cyst TSH.

Clinical Significance of Thyrotropin Measurement as a Screening Test in Ambulatory Patients.: Young Kee Shong, Hong Kyu Kim, Ghi Su Kim, Dae Hyuk Moon; J Korean Endocr Soc. 1994;10(3):191-199. Published online November 6, 2019

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Abstract PDF: The objective of this study is to determine the clinical significance of thyrotropin(TSH) measurement as a screening test in ambulatory patients. One hundred and nintynine patients with abnormal TSH levels detected at routine examinations were studied. The patients were examined and histories about the recent medications and nonthyroidal illness were taken. Additional thyroid tests were done including measuments of total T_3, free T_4, antithyroid autoantibodies, thyroid scan and radioiodine uptake. Of the total 199 patients, 107(54.7%) had thyroid diseases. 49 out of 101 patients with subnormal TSH had thyroid diseases, and the remainder had supressed TSH due to medications, associated nonthyroidal illness, and normal variations. 58 out of 99 patients with elevated TSH had thyroid diseases. Of those 47 patients whose TSH level was below 0.05 mIU/L, functional sensitivity of TSH assay in our laboratory, 37 had thyroid diseases. Of those 19 patients whose TSH level was above 7.0mIU/L, two times of upper normal limit, all had thyroid iseases.Simultaneous measurement of free T_4 disclosed 50(25.1%) out of total 199 patients with abnormal TSH levels had abnormal free T_4 values which is regarded as evidence of clinical thyroid dysfunction. In summary, a single measurement of TSH level alone seems to have high sensitivity but low specificity. Simultaneous measurement of free T_4 can reasonably compensate the low specificity of TSH measurement. In case of ambulatory patients without significant nonthyroidal illness, TSH values below functional sensitivity or above twice upper normal limit may predict thyroid disease and dysfunction with reasonable specificity.

Case Report

The Effect of Octreotide LAR on GH and TSH Co-Secreting Pituitary Adenoma.: Nam Keong Kim, Yu Jin Hah, Ho Young Lee, Sang Jin Kim, Mi Kyung Kim, Keun Gyu Park, Ealmaan Kim, Hyukwon Chang, Hye Soon Kim; Endocrinol Metab. 2010;25(4):378-381. Published online December 1, 2010; DOI: https://doi.org/10.3803/EnM.2010.25.4.378

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Abstract PDF: Growth hormone (GH) and thyroid stimulating hormone (TSH)-secreting pituitary adenomas are very rare and they account for only 0.5% for all pituitary adenomas. These adenomas are usually treated with surgery, but this surgery is not easy because the tumor is usually huge and invasive. We reported here on a case of a GH-TSH-secreting adenoma in a 23-year-old male patient who was initially treated with octreotide LAR. He presented with symptoms of headache, palpitation and a visual defect that he had for the 3 months. He had hypertrophy of the frontal bone and enlargement of both the hands and feet. The visual field test showed bitemporal hemianopsia. The laboratory examinations showed high serum levels of free T4, TSH and free alpha-subunit. Additionally, the serum levels of GH and insulin-like growth factor-I (IGF-I) were increased. GH was not suppressed below 1microg/L by an oral 75g glucose loading test, and TSH was not stimulated by thyrotropin-releasing hormone (TRH). Because sellar MRI showed invasive macroadenoma encasing the vessels, we initially tried octreotide LAR for treatment. A year later, the IGF-I and thyroid function tests were normalized and the size of the tumor was reduced with cystic change. The symptoms of palpitation and headache were improved without a change of the visual field defect.

Original Articles

Clinical Usefulness of the Second Generation TSH-Binding Inhibitory Immunoglobulin Assay Using Recombinant Human TSH Receptor in Patients with Graves' Disease.: Jung Eun Huh, Ji Hye Suk, Mi Kyung Kim, Im Jeong Choi, Seok Man Son, In Joo Kim, Yong Ki Kim; J Korean Endocr Soc. 2008;23(3):179-185. Published online June 1, 2008; DOI: https://doi.org/10.3803/jkes.2008.23.3.179

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Abstract PDF

BACKGROUND
AND AIM: Detection of TSH receptor antibody in patients with Graves' disease (GD) has been widely used in clinical practice. This has been performed mostly by commercial radio-receptor assays that measure TSH-binding inhibitory immunoglobulin (TBII) with using porcine TSH receptor as the ligand. To increase the sensitivity of the assay, many research groups have tried to replace the porcine source of TSH receptor with recombinant human TSH receptor. In this study we evaluated the clinical usefulness of the second generation TBII assay, which uses recombinant human TSH receptor, for making the diagnosis of GD, as compared to the conventional TBII assay. MATERIALS AND METHODS: We obtained sera from 76 patients with newly diagnosed or relapsing GD without or with less than 4 weeks of antithyroid drugs, and 54 patients with Hashimoto's thyroiditis who had not received thyroid hormone treatment or quit thyroid hormone more than 3 months before. TBII was measured by using both the conventional porcine TBII assay (pTBII) and the human recombinant TBII assay (hTBII). TBII was also measured in the sera from 66 healthy controls. RESULTS: The cut-off values of the pTBII and hTBII assay were defined as two geometric standard deviations from the geometric mean of the values in healthy controls, and these values were 10.8 IU/L and 1.0 IU/L, respectively. The sensitivity was 62% (47/76) for pTBII, as compared to 100% (76/76) for the hTBII, for diagnosing GD. Of the 54 patients with Hashimoto's thyroiditis, 3 (5.6%) and 7 (13.0%) patients had positive pTBII and positive hTBII, respectively. CONCLUSION: These data showed that the hTBII assay was a comparable method in terms of the sensitivity for the diagnosis of GD, as compared to the pTBII assay. It can be suggested that this new hTBII assay, rather than the pTBII assay, should be more widely used as the first line diagnostic test for GD.

Citations

Citations to this article as recorded by

Changes in Thyroid Peroxidase and Thyroglobulin Antibodies Might Be Associated with Graves' Disease Relapse after Antithyroid Drug Therapy
Yun Mi Choi, Mi Kyung Kwak, Sang Mo Hong, Eun-Gyoung Hong
Endocrinology and Metabolism.2019; 34(3): 268. CrossRef
Usefulness of Measuring Thyroid Stimulating Antibody at the Time of Antithyroid Drug Withdrawal for Predicting Relapse of Graves Disease
Hyemi Kwon, Won Gu Kim, Eun Kyung Jang, Mijin Kim, Suyeon Park, Min Ji Jeon, Tae Yong Kim, Jin-Sook Ryu, Young Kee Shong, Won Bae Kim
Endocrinology and Metabolism.2016; 31(2): 300. CrossRef
Clinical Applications of Thyrotropin Binding Inhibitor Immunoglobulin (TBII) Assays
Won Bae Kim
Journal of Korean Endocrine Society.2008; 23(3): 174. CrossRef

Crosstalk Between cAMP and Phosphoinositide System in Signal Transduction Pathways Through TSH Receptor.: Byung Sool Moon, Young Joo Park, Seong Yeon Kim, Bo Youn Cho, Hong Kyu Lee, Do Joon Park; J Korean Endocr Soc. 2003;18(4):404-413. Published online August 1, 2003

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Abstract PDF: BACKGROUND
TSH stimulates both the adenyl cyclase and phospholipase C (PLC) pathways by binding to a single cell surface receptor that is coupled to G protein, and we examined crosstalk between these two signaling pathways. METHODS: FRTL-5 rat thyroid cells were grown in 6H medium, then incubated with 5H medium before the stimulation. Then cells were incubated for 24 hours with 5H mix containing 1 mCi/L myo-(2-N-3H) inositol. After pretreatment of 100 microM Rp-cAMP, 100 microM forskolin, 50 nM staurosporine, or 100 nM PMA (phorbol-12-myristate-13-acetate), TSH were added in different experiments. After 30 min at 37 degrees C, cells were disrupted and IP formation was determined. RESULTS: Stimulation with 100 microU/mL TSH resulted in a 1.65 fold increase in IP generation. In pursuing the possibility that the two post-receptor events might be linked in some way, we examined the effect of exogenously administrated Rp-cAMP, protein kinase A antagonist, and forskolin, a direct stimulant of protein kinase A, on IP generation achieved at a dose of 100 microU/mL TSH. The pretreatment of 100 M Rp-cAMP at a concentration sufficient to inhibit protein kinase A enhanced TSH-induced IP production. This effect of Rp-cAMP was dose-dependent. Forskolin attenuatedTSH-stimulated increases in phosphatidylinositide turnover. PMA, a protein kinase C (PKC) activator and staurosporine, a PKC inhibitor did not affect TSH-induced IP generation. CONCLUSION: These data suggested that activation of adenylate cyclase/cAMP post-receptor signalling casacde, which results in the protien kinase A activation, has an inhibitory effect on IP turnover activated by TSH.

Regulatory Mechanism of p66 Shc Expression by TSH in FRTL-5 Cells.: Young Joo Park, Eun Shin Park, Tae Yong Kim, Yun Yong Lee, Seon Hwa Lee, Do Joon Park, Chan Soo Shin, Kyoung Soo Park, Seong Yeon Kim, Hong Kyu Lee, Bo Youn Cho; J Korean Endocr Soc. 2003;18(1):45-55. Published online February 1, 2003

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Abstract PDF: BACKGROUND
Thyroid goiters are very common, however, the mechanism of development is not fully understood. A TSH receptor has been known to activate two different signaling pathways the cAMP/protein kinase A(PKA) and phospholipase C(PLC)/protein kinase C(PKC) systems. However, both systems are limited in the degree to which they explain the discrepancy between a goiter and TSH receptor activation. It has recently been reported that the expression of p66 Shc was increased by TSH stimulation in thyrocytes, suggesting that the p66 Shc molecule may play a critical role in the transition of the TSH-induced growth signals. METHODS AND RESULTS: In this study, we examined the expression of p66 Shc by stimulation of TSH, and the regulatory mechanisms of the TSH-induced expression of the p66 Shc in FRTL-5 cells. In FRTL-5 cells, TSH could increase the expression of the p66 Shc, and the this expression was decreased to basal levels after the removal of TSH. The TSH-induced p66 Shc expression was competitively inhibited by TSH receptor blocking antibodies. The increments of the expression of the p66 Shc protein caused by TSH were both time and concentration dependent, and it was same in the mRNA levels. Cholera toxin increased the expression of the p66 Shc, while pertussis toxin did not. The activators of the cAMP/PKA pathway (8-bromo-cAMP and forskolin) also stimulated the expression of p66 Shc, and the PKA inhibitor H89 decreased the expression, while the inhibition of the PKC pathway by GF109203X, or PMA, affected the expression of p66 Shc very little. CONCLUSION: Our data suggests that p66 Shc may play an important role in regulating the growth of thyrocytes. The TSH receptor - Gs protein - adenylate cyclase - cAMP - PKA pathway mainly mediates the TSH effects on the expression of p66 Shc molecules.

Usefulness of Immunoglobulin Fraction Precipitated with Polyethylene Glycol in Assay for TSH Receptor Antibodies using Chinese Hamster Overy Cells Expressing Human TSH Receptors.: Won Bae Kim, Hyun Kyung Chung, Chang Soon Koh, Chang Hoon Yim, Do Joon Park, Bo Yeon Cho, Hong Gyu Lee; J Korean Endocr Soc. 1998;13(2):167-180. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Graves' disease and primary myxedema are thought to be caused by the action of TSH receptor autoantibodies(thyroid stimulating antibody; TSAb & thyroid stimulation blocking antibody; TSBAb). Thus, detection of these antibodies is crucial in diagnosis and in follow up of those patients. Recently, a sensitive method using human TSH receptor transfected Chinese Hamster Ovary(CHO) cells has been developed. However, the complexity of IgG purification procedure is considered as a limitation for its clinical application as a routine test. The aim of this study is to determine whether polyethylene glycol(PEG)-precipitated immunogiobuIin fraction could substitute for purified IgG. METHODS: We developed optimal conditions for TSAb and TSBAb assays using crude, PEG precipitated immunoglobulin fraction; and evaluated the correlation of TSAb and TSBAb activities between thase measured using crude immunoglobulin fraction and purified IgG to clarify the usefulness of PEG-precipitated immunoglobulin fraction. TSH receptor expressing wild type CHO cells were used in TSAb and CHO cells expressing chimeric TSH receptor(Mc2; 90-165 amino acid residues were substituted by those of rat LH/CG receptar) were used in TSBAb assay to minimize the possible disturbing effects of TSAb in serum. RESULTS: The optimal serum amount for TSAb and TSBAb assay using PEG-precipitated immunoglobulin fraction were 250mL serum equivalent/well and 50mL serum equivalent/well, respectively. The optimal incubation time for both assays were 2 homs, and aptimal ccrncentration of bTSH for TSBAb assay was 0.1U/L. TSAb activities measured with PEG-precipitated immunoglobulin were significantly correlated with those measured with purified IgG in 26 patients with Graves diseases(r=0.93, p<0.001). Although TSBAb activities measured using PEG-precipitated imrnunoglobulin were conelated with those measured using purified IgG in 20 patients with primary myxedema(r=0.86, p<0.001), the positive rate in TSBAb assay using PEG-precipitated immunoglobulin was lower than that of usmg purified IgG(20% v.s. 65%) because of negative conversion of TSBAb activities in samples with weakly positive TSBAb activities measured using purified IgG. CONCLUSION: PEG-precipitated immunoglobulin fraction could be used instead of purified IgG in TSAb assay using hTSHR-tranasfected wild type CHO cells with equal sensitivity and specificity. This simple and practical TSAb assay using PEG-precipitated immunoglobulin in hTSHR-transfected CHO cells would be useful in clinica1 practiee.

Heterogeneity of TSH Receptor Autoantibodies in Autoimmune Thyroid Disease.: Won Bae Kim, Bo Youn Cho, Kyoung Ah Kim, Jae Hoon Chung, Young Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim; J Korean Endocr Soc. 1997;12(2):176-193. Published online January 1, 2001

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Abstract PDF: BACKGROUND
It has been known that most of thyroid stimulating antibodies (TSAbs) may interact with epitopes near N-terminal, and thyroid stimulation blocking antibodies (TSBAbs) near C-terminal on the extracellular domain of TSH receptor. However, many authors have reported different results about epitopes reacting with TSH receptor autoantibody (TRAb). TSBAbs inhibit thyroid stimulation of TSH and TSAbs at the receptor level. However, it has been reported that there are some TSBAbs which bind to the other sites, not TSH receptor, or block post-reeeptor process. These findings raise the possibility that TRAbs may be heterogeneous according to the mechanism of action. In order to investigate the heterogeneity of TRAb, we undertook immuno-precipitation using synthetic peptides of TSH receptor and measured TRAb activities by FRTL-5 cells and chimeric CHO cells. METHODS: We studied 102 patients with autoimmune thyroid disease (Graves disease 32, Hashimotos thyroiditis 29, atrophic thyroiditis 41) and 35 healthy persons. Three synthetic peptide fragments of TSH receptor were used to perform immunoprecipitation with serum or IgG of patients and healthy persons, TSAb and TSBAb activities were measured by FRTL-5 cells and CHO cells transfected with wild-type and 2 mutant TSH receptor cDNA (Mc2, Mc1+2). Mc2 and Mcl+2 were rnade to substitute amino acid residues of 90-165, 8-165 of the TSH receptor with corresponding residues of LH/CG receptor, respectively. RESULTS: Two out of 10 IgGs extracted from Graves disease and 2 out of 9 IgGs from atrophic thyroiditis had specific bidings over 0.84% in immunoprecipitation with peptide I (amino acid residue 35-50). Four out of 18 IgGs from Graves disease, 9 out of 41 IgGs from atrophic thyroiditis, and 6 out of 14 IgGs from Hashimotos thyroiditis had specific bidings over 0.84% in immunoprecipitation with peptide II (amino acid residue 317-332). Only 2 out of 10 IgGs from Graves disease had specific bidings over 0.84% in immunoprecipitation with peptide III (amino acid residue 341-358). When 10 IgGs extracted from Graves disease were reacted with wild-type, Mc2, and Mcl+2 CHO cells, 7 IgGs in wild-type and 4 IgGs in Mc2 had positive for TSAb activities. In 10 IgGs from atrophic thyroiditis, 5 in wild-type, 5 in Mc2, and 3 in Mcl+2 CHO cells had positive for TSBAb activities. In Hashimoto's thyroiditis, only 1 with hyperthyroidism had positive for TSAb activity in wild-type and 1 with hypothyroidism had positive for TSBAb activities in both of wild-type and Mc2 CHO cells. Therefore, patients with Graves disease were divided into at least 3 groups according to the TSAb activities measured by wild-type, Mc2, Mcl+ 2 CHO cells and TBII activities. And patients with atrophic thyroiditis were divided into at least 4 groups according to the TBII activities, TSBAb activities by wild-type, Mc2, Mcl+2 CHO cells and FRTL-5 cells. CONCLUSION: From these results, epitopes of TSH receptor reacting with TSAb or TSBAb in autoimmune thyroid disease may be scattered in the TSH receptor, although epitopes of TSAb tend to be near N-terminal and those of TSBAb near C-terminal. Graves disease or atrophic thyroiditis were divided into 3 or 4 groups according to the TBII and TRAb activities. Therefore, TRAb detected in autoimmune thyroid disease may be heterogenous.

Measurements of Thyroid Stimulation Blocking Antibody Activities by Chinese Hamster Ovary ( CHO ) cells Expressing Human TSH Receptors in Patients with Primary Hypothyroidism.: Won Bae Kim, Bo Youn Cho, Do Joon Park; J Korean Endocr Soc. 1997;12(1):18-32. Published online January 1, 2001

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Abstract PDF: BACKGROUND
The Chinese hamster ovary cells transfected with human TSH receptor cDNA (hTSHR-CHO), expressing functional human TSH receptors, are known to be more sensitive in detection of thyroid stimulating antibodies than FRTL-5 cells. There has been no report on the usefulness of these cells to measure thyroid stimulation blocking antibody (TSBAb) activity which is frequently found in patients with primary myxedema, METHODS: We established the optimal assay condition of measurement of TSBAb using hTSHR-CHO cells, and simultaneously measured TSBAb activities with FRTL-5 cells and with hTSHR-CHO cells in 49 patients with primary myxedema, compared them with their thyrotropin binding inhibitor immunoglobulin (TBII) activities. RESULTS: 1) hTSHR-CHO cells specifically bound bTSH and were stimulated by bTSH in terms of cyclic AMP generation in a dose dependent manner. 2) Myxedema IgG suppressed TSH-stimulated cAMP production of hTSHR-CHO cells in a dose dependent manner reaching plateau at the concentration of I g/L. Normal pooled IgG has no suppressive action at the concentration of less than 1 g/L, but caused significant suppression at the concentration of greater than 1g/L. 3) TSBAb activities measured by hTSHR-CHO cells in 49 patients with primary myxedema were as follows: Four of 25 TBII-negative cases (16%) and 22 of 24 TBII-positive cases (92%) had TSBAb activities. Most of TSBAb positive patients (95%), especially in TBII positive cases, showed very high activities of more than 90%. 4) TSBAb activities measured by hTSHR-CHO cells and those by FRTL-5 cells were both positive in 24 patients (49%), both negative in 18 patients (37%), and were discrepant in 7 patients (14%). The TSBAb activities measured with hTSHR-CHO cells and those measured with FRTL-5 cells were significantly correlated (r=0.71, p< 0.01). 5) Forty five percent of patients with primary myxedema had all of 3 kinds of activities (TBII, hTSHR-CHO cell TSBAb, FRTL-5 cell TSBAb), 37% of them had none of 3 activities and 18% of them had 1 or 2 kinds of activities only. CONCLUSION: The usefulness of hTSHR-CHO cells in measurements of TSBAb activities were confirmed. The TSBAb activities of most patients with primary myxedema measured by hTSHR-CHO cells were concordant with those measured by FRTL-5 cells. However, a small subset of patients (18%) had discrepant results in assays of TSH receptor antibodies according to the differences in TSH receptors (rat, human and porcine) used in assay. Such discrepancy may be explained by heterogeneity in epitopes for blocking TSH receptor antibodies.

Differential Roles of Transcriptional Coactivators: CBP and CIITA on GAS (Interferon-r Activated Site) - Mediated Transcription in Thyroid Cells.: Eun Shin Park, Ho Kim, Soon Hee You, Soo Jung Park, Hyun Jin Kim, Soo Heung Chae, Do Hee Kim, Hee Jeong Han, O Yu Kwon, Young Kun Kim, Minbo Shong, Heung Kyu Ro; J Korean Endocr Soc. 1999;14(3):493-504. Published online January 1, 2001

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Abstract PDF: BACKGROUND
In the previous studies, we identified that the interferon-gamma activated sequence (GAS) in the 5-flanking region of rat ICAM-1 gene is major element for interferon-y-inducible expression of the gene in rat thyroid cells, FRTL-5. We here, investigated the role of transcriptional coactivators, CBP (CREB binding protein) and CIITA (class II transactivator) in the modulation of the activity of GAS which could interacts with signal transducers and activators of transcription-1 and 3 (STAT1 and STAT3). METHODS: The expression of CBP RNA and protein were quantitated in FRTL-5 after stimulation with interferon-y (IFN-gamma), thyroid stimulating hormone (TSH), forskolin and methimazole. Direct association of CBP with STAT were analyzed by irnmunoprecipitation. The transcriptional roles of CBP and CIITA in the regulation of GAS were assessed by the cotransfection with their expression vectors with reporters; 5-deletion constructs of rat ICAM-1 promoter or 8xGAS-luc constructs, into FRTL-5 thyroid cells. RESULTS: The level of CBP RNA and protein were not changed by the treatment with TSH, IFN-y, forskolin and methimazole in FRTL-5, FRT and BRL liver cells. The CBP could be directly associated with STAT1. Furthernmore, the overexpression of CBP significantly increases the both promoter activities; rat ICAM-1 gene promoter which has GAS element and 8xGAS-luc cassette constructs. However the cotransfection of CI1TA decreased the constitutive and CBP-mediated transactivation of rat ICAM-1 promoter and SxGAS-luc cassette constructs. CONCLUSION: We identified that the two transcriptional coactivators; CBP and CIITA has differential roles in the regulation of transcriptional activity of GAS drived promoter. CBP increases the GAS activity through the direct binding with STATl, but CIITA inhibited the CBP-mediated transactivation of GAS activity.

Case Reports

A Case of Ioslated TSH Deficiency.: Hyun Kim, Won Seob Kim, Soo Jin Choi, Dong Yoon Kim, Se Hyun Kim, Seung Min Park, Wan Koo Lee, Young Nam Kim; J Korean Endocr Soc. 1999;14(2):392-395. Published online January 1, 2001

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Abstract PDF: Although complete or partial deficiency of anterior pituitary hormone is well known,but isolated TSH deficiency is relatively rare throughout the world. Hypothyroidism due to isolated TSH deficiency is diagnosed by 1)symptoms or signs of thyroid deficiency, 2)demonstration of an absent or impaired TSH response to TRH stimulation, 3)intact other pituitary hormones. We report a case of hypothyroidism due to isolated TSH deficiency. The patient was 75 years old man and his complaints were generalized edema and weight gain. On laboratory study, T3, T4, TSH was low and TSH response to TRH stimulation was blunted, but other piutuitary hormones were intact. After thyroxine replacement, TFT and his symptoms were recovered.

A Case of Graves' Disease with Spuriously Elevsted TSH due to Interference of Heterophilin Actibodies.: Jeong Hee Han, Sung Jin Lee, Young Rok Sin, Eun Ju Lee, Eun Sook Kim, Sang Wook Kim, Jin Yub Kim, Il Min Ahn; J Korean Endocr Soc. 1999;14(1):160-164. Published online January 1, 2001

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Abstract PDF: Thyroid-stimulating hormone (TSH) is the most sensitive marker reflecting thyroid function. TraditionaUy, TSH concentration was measured by the method of RadioImmunoAssay (RIA) with the detection limits around 1 to 2 mIU/L, which was unable to differentiate hyperthyroid status. Since 1980s, owing to the sensitive assay for TSH, immunoradiometric assay (IRMA), it has been possible to detect low concentration of TSH by 0.001 mlU/L. TSH is composed of two glycopeptide subunits, a-subunit and B-subunit. Monoclonal antibodies, directed against two different sites of the TSH peptides, are used in IRMA. One antibody is directed toward the specific B-subunit of TSH molecule and is used to extract it from serum, a second antibody labelled with a radioactive material is then attached to the separated TSH to form "sandwhich" molecule that can be measured. Generally, mouse monoclonal antibodies are used as capture and detection antibodies. Infrequently, when there is heterophilic antibody, i.e. human anti-mouse antibody (HAMA), TSH can be measured as spuriously elevated, since HAMA may form a link between the signal and capture molecules. We report a case of inappropriately elevated TSH concentration due to heterophilic antibody, later diagnosed as Graves disease. A 41-year-old woman visited our clinic with the chief complaints of hand tremor, hyperphagia, weight loss for 3 months. Two years earlier, she underwent total colectomy due to colon cancer and had treat on multiple chemotherapies. The results of thyroid function test shows that TSH was 0.77 mIU/L, free T was 7.1 ng/dL (0.8~1.9), free T was 11.3 pg/mL (0.2~5.5). Thyroid specific auto- antibody results were anti-Tg-Ab 21.3 m/mL(0 100), anti-TPO-Ab 87.9m/mL(0100), TBIAb 7.8% (-15/15). Thyroid scan showed that radioactiveiodine uptake was increased and thyroid gland wasenlarged diffusely. Because TSH level was elevated, further evaluations were performed to differentiate with TSH producing pituitary tumor and pituitary resistance to thyroid hormone. Sellar MRI was normal, TRH stimulation test showed flat response. Since spurious elevation of TSH is possible at the presence of hetrophilic antibody, we rechecked TSH concentration after adding mouse monoclonal antibody to the patients serum with result of TSH less than 0.05 mIU/L. She was able to be diagnosed as Graves disease, and started with methimazole. Three months later, thyroid function test showed that TSH was 10.5 mIU/L, free T4 was 1.0 ng/dL, free T3 was 4.0 pg/mL. TSH level after removal the effect of heterophilic antibody with mouse monoclonal antibody was 0.71 mIU/L. Neutropenia was developed 5 months after methimazole therapy, to stop antithyroid medication. With the plan of radioactive iodine therapy if she relapses, she is being followed with periodic thyroid function test. We report a case of Graves disease with spuriously elevated TSH due to the effect of heterophilic antibodies.

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