Endocrinology and Metabolism

Volume 18(4); August 2003

Review Articles

Perspectives on Molecular and Genetic Researchs on Ret/ptc-induced Papillary Thyroid Cancer.: Dong Wook Kim, Min Ho Shong; J Korean Endocr Soc. 2003;18(4):337-341. Published online August 1, 2003

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Abstract PDF: No abstract available.

Somatostatin Receptor.: Eunhee Kim, Sookjin Sohn, Mina Lee, Heesoon Park, Jeechang Jung, Seungjoon Park; J Korean Endocr Soc. 2003;18(4):342-355. Published online August 1, 2003

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Abstract PDF: No abstract available.

The Impaired Glucose Metabolism in Patients with Cushing's Syndrome.: Hyung Joo Park, Joong Yeol Park; J Korean Endocr Soc. 2003;18(4):356-359. Published online August 1, 2003

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Abstract PDF: No abstract available.

Original Articles

Analysis of Ret Proto-oncogene Mutation in Korean Patients with Medullary Thyroid Carcinomas.: Hyung Hoon Kim, Hyun Jin Kim, Yun Jae Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Kwang Won Kim, Chang Seok Ki, Jong Won Kim, Jae Hoon Chung; J Korean Endocr Soc. 2003;18(4):360-370. Published online August 1, 2003

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Abstract PDF: BACKGROUND
Medullary thyroid carcinomas (MTC) have been reported as hereditary in about 25 ~30% of cases. The identification of germline mutation in RET proto-oncogene is important in the diagnosis of hereditary MTC, and occurs in three forms: MEN 2A, MEN 2B and familial MTC (FMTC). To evaluate the prevalence of the relationship of RET proto-oncogene mutation and genotype-phenotype was studied in Korean patients with MTC. METHODS: Genomic DNA was obtained from 29 patients, with MTC, who underwent a total thyroidectomy, between 1997 and 2003, at the Samsung Medical Center. There were 7 male and 22 female patients, with an average age of 39, ranging from 20 to 60 years. Exon 10, 11, 13, 14 and 16 of the RET proto-oncogene were amplified, with specific primers, using PCR. A sequencing analysis was performed on the PCR product using an automatic sequencing analyzer. RESULTS: Nine of the 29 patients (31%) were identified as having RET mutations. The average age of these 9 patients was 33 years, ranging from 20 to 51, with a female to male ratio of 2. Five patients had MEN 2A and one had FMTC, with the other 3 thought to have non-hereditary (sporadic) MTC. The 4 patients with MEN 2A had RET mutations on codon 634 of exon 11 (2 patients, C634R; 2 patients, C634Y) and the other patient on codon 618 of exon 10 (C618R). One patient with FMTC had a mutation on codon 634 (C634W). Three patients with sporadic MTC had RET mutations on codon 634 (2 patients, C634Y; 1 patient, C634S). However, no genotype- phenotype relationship could be found, due to the limited number of patients. CONCLUSION: Thirty-one percent (9/29) of the patients with MTC had RET proto-oncogene mutations. Three-quarters (9/12) of the Korean patients with MEN 2A, including another 7 patients reported in 3 papers in Korea, had RET mutations on codon 634 of exon 11 (4 patients, C634R; 4 patients, C634Y; 1 patient, C634W), but a quarter (3/12) had mutations on codon 618 of exon 10 (2 patients, C618R; 1 patient, C618S). Although no relations could be found between the genotypes and phenotypes, extensive prospective studies will be required to verify this.

Search for "Proximal Histidine" of Thyroperoxidase Using Site Directed Mutagenesis.: Won Bae Kim, Young Kee Shong; J Korean Endocr Soc. 2003;18(4):371-378. Published online August 1, 2003

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Abstract PDF: BACKGROUND
Thyroperoxidase (TPO), a transmembrane heme containing glycoprotein, catalyzes iodide organification and thyroid hormone synthesis. It is a single peptide making a loop with more than one disulfide bond. The tertiary conformational structure is essential for its enzymatic activity and immunogenicity. The proximal histidine is thought to play a major role in enzymatic activity since it is linked to the iron center of the heme. The crystal structure of TPO has not yet been reported, but some have suggested histidine 407 be a putative proximal histidine based on comparison of a.a. sequence for TPO and that for myeloperoxidase. METHODS: The putative histidine 407 and nearby histidine 414 were mutated to arginine to verify their role as the proximal histidine. Using site directed mutagenesis of wild type, human TPO cDNA, mutants H407R and H414R were made. Mutant cDNAs were transiently transfected into COS-7 cells, and the TPO enzyme activities were measured by guaiacol assay. Four cysteine residues around the putative proximal histidines were mutated to serine and their enzymatic activities were measured to check if they were involved in the formation of intra-molecular disulfide bonds. RESULTS: TPO protein expression of H407R- and H414R- transfected cells was confirmed by Western blot, using Hashimoto's IgG as primary antibody. Both the mutants H407R and H414R showed significant peroxidase enzymatic activity, although lower than those of the wild type. None of the cysteine mutants, C375S, C389S, C598S, and C655S, were detected by Hashimoto's IgG ordisplayed any enzymatic activity. CONCLUSION: These data suggest that neither histidine 407 nor histidine 414 functions as the "proximal histidine" in human TPO. All the cysteine residues checked (375, 389, 598, 655) might be involved in the formation of disulfide bonds in TPO molecules, but this hypothesis could not be confirmed. A further search for the other putative histidine residues using the same strategy is needed to define the structure-function relationship in the human TPO molecule.

The Effect of T3 on Thyroid Hormone Receptor Dynamics in Thyroid Hormone Response Element of Chicken Lysozyme Silencer.: Seong Jin Lee, Cheol Young Park, In Kyung Jeong, Eun Gyung Hong, Cheol Soo Choi, Hyeon Kyu Kim, Doo Man Kim, Jae Myung Yoo, Sung Hee Ihm, Moon Gi Choi, Hyung Joon Yoo, Sung Woo Park, P Reed Larsen; J Korean Endocr Soc. 2003;18(4):379-391. Published online August 1, 2003

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Abstract PDF: BACKGROUND
The regulation of gene transcription can be controlled by both positive (enhancer) and negative (silencer) regulatory sequences. Several enhancer and silencer elements have been described in the 5' region of the chicken lysozyme gene. The silencer located at -2.4 kb upstream of the chicken lysozyme gene is composed of two separate modules (F1 and F2) that can function as silencers by themselves, but also show synergistic repression after multimerization. The F1 module is bound by a protein termed NeP1 and F2 module, a F2 thyroid hormone response element (F2-TRE), and can be bound by the thyroid hormone receptor (TR). F2-TRE has an inverted palindromic structure, with high affinity to TR. Although many current reported results have tried to explain the regulatory mechanism of chicken lysozyme gene expression due to the thyroid hormone, there have been few studies that clarify the TR dynamics in the F2-TRE of the chicken lysozyme gene, either with or without exposure of the thyroid hormone. Here, the changes in the TR binding patterns in the F2-TRE of the chicken lysozyme gene are described, both before and after T3 stimulation over time. METHODS: Using the stably transfected rat pituitary somatotroph tumor cell line, GC8 cells, with the F2-TRE inserted 5' to the thymidine kinase (TK) promoter, together with a mouse TRalpha- expressing plasmid, a chromatin immunoprecipitation (ChIP) technique was employed to reveal the TR-TRE interaction before and after T3 stimulation. Following the cross-linking and sonication of the cells, the immunoprecipitation was performed overnight, at 4 degrees C, with TRalpha1, TRbeta1 and TRbeta2 antibodies, respectively. The binding patterns and amounts of TRalpha1, TRbeta1 and TRbeta2 to the F2-TRE, before and after 12 hours of 100 nM T3 stimulation, were analyzed using conventional and quantitative real-time polymerase chain reactions (RQ-PCR). The ChIP technique was used to give a basal value for 20 minutes and 1, 2, 4, 6, 8 and 12 hours after the 100 nM T3 stimulation, and RQ-PCR was then performed. Western blot with TRalpha1, TRbeta1 and TRbeta2 antibodies were also performed. RESULTS: After 12 hours of 100 nM T3 stimulation of the GC8 cells, the TRalpha1 and TRbeta2 binding to the F2-TRE increased, but the TR 1 binding to the F2-TRE decreased, by conventional PCR. Although all the TR isoforms were bound to the F2-TRE by RQ-PCR, the TR 1 binding to the F2-TRE, after 12 hours of 100 nM T3 stimulation, was significantly increased (1.01-->2.73, delta=+170.3%, p<0.05), but the change in the amount of TRbeta2 binding was not significant (2.53-->2.98, delta=+17.8%). The TRbeta1 binding was significantly decreased compared with that of the basal level (4.59-->2.06, delta=-55.1%, p<0.05). The total TR bindings to the F2-TRE had a tendency to decrease after 12 hours of 100 nM T3 stimulation (8.13-->7.77, delta=-4.4%). The binding patterns and amounts of TRalpha1, TRbeta1 and TRbeta2, both before and after the 100 nM T3 stimulation, were also identified over time. While the TRbeta1 bindings to the F2-TRE after 1 hour of 100 nM T3 stimulation were acutely reduced, those of the TRalpha1 at 20 minutes and 6 hours were increased. The TRbeta2 bindings showed a maximal increase at 20 minutes. The directions of the TR binding patterns, between the before and after 2 hours of 100 nM T3 stimulation, were identical to those for between 4 and 6 hours of T3 stimulation. There was no significant difference in the TR bindings to the F2-TRE in relation to the amounts (1.5 vs. 4.5 microliter) of TR antibodies used during the ChIP assays. The Western blots showed no significant change of the levels of each TR isoform proteins, either before or after 12 hours of exposure to 100 nM T3. CONCLUSION: These results show the dynamic binding patterns of the TR isoforms to the F2-TRE of the chicken lysozyme gene, both before and after T3 stimulation, over time. Further investigation, however, will be needed to clarify the mechanisms of our observations. The ChIP technique may then be used to reveal the dynamic models of the cofactors, as well as TR isoforms, in the TR-regulated transcription machinery.

The Change of Insulin Sensitivity and Insulin Secretion According to Glucose Metabolism Status in Patients with Cushing's Syndrome.: In Kyung Jeong, Sung Hoon Kim, Jae Hoon Chung, Yong Ki Min, Myung Shik Lee, Moon Kyu Lee, Hyung Joon Yoo, Kyu Jeong Ahn, Jung Hynun Noh, Dong Jun Kim, Kwang Won Kim; J Korean Endocr Soc. 2003;18(4):392-403. Published online August 1, 2003

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Abstract PDF: BACKGROUND
Glucocorticoid plays an important role in the control of carbohydrate metabolism. Patients with Cushing's syndrome have been reported to have an increased incidence of carbohydrate intolerance due to peripheral insulin resistance and hyperinsulinemia, although the exact incidence and nature of this disorder have remained unclear. Few results have been published about insulin resistance and insulin secretion according to the level of glucose concentration, or about the reversibility of such defects in patients with Cushing's syndrome. METHODS: To assess the effect of glucocorticoid on the insulin sensitivity and insulin secretion in Cushing's syndrome, 15 patients with Cushing's syndrome were classified into 3 groups (normal glucose tolerance: NGT, impaired glucose tolerance: IGT, diabetes: DM) according to the degree of glucose tolerance based on the oral glucose tolerance test (OGTT). Insulin modified, frequentlysampled, intravenous glucose tolerance test (FSIGT) was performed before and after curative surgery on these patients and on 15 healthy control subjects. Data were evaluated by non-parametric statistical analysis. RESULTS: 1) Among the 15 patients with Cushing's syndrome, 3 (20%) were NGT, 4 (27%) IGT, and 8 (53%) DM, based on OGTT. Twenty-four hour urinary free cortisol (UFC) was significantly higher in the DM group. 2) Insulin sensitivity index (SI) of Cushing's syndrome was significantly lower than that of the control group (P=0.0024), but was not significantly different among the three Cushing's syndrome groups of NGT, IGT and DM. 3) Glucose mediated glucose disposal (SG) (Ed- confirm this abbreviation; it does not seem to match the definition) of Cushing's syndrome was not significantly different from that of the control group. 4) Insulin secretion (AIRg) of Cushing's syndrome tended to be high, but it was not significantly different from that of control. However, according to the level of glucose concentration there was significant difference in AlRg among the three Cushing's syndrome groups (P=0.0031); AIRg of DM was significantly lower than that of NGT. 5) After surgical treatment, parameters of insulin sensitivity and insulin secretion were normalized in 6 cured patients; 1 with NGT, 1 with IGT, and 4 with DM, preoperatively. Median SI of all 6 patients was significantly improved up to the normal range postoperatively (P=0.0022). Median AIRg of these 6 patients was balanced around that of normal control postoperatively (P=0.0286). CONCLUSION: Eighty percent of patients with Cushing's syndrome had abnormality of carbohydrate metabolism. Insulin sensitivity was significantly decreased in Cushing's syndrome. Insulin secretion was significantly higher only in the NGT and IGT groups of Cushing's syndrome. As the hypercortisolemia is exacerbated, insulin secretion is significantly decreased and causes DM, suggesting that glucocorticoid has a direct or indirect toxic effect on the pancreatic beta cell.

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.

Case Reports

A Case of Riedel's Thyroiditis in a Patient with a History of Subacute Thyroiditis.: Chul Sik Kim, Sung Ju Lee, Jong Suk Park, Joo Young Nam, Dol Mi Kim, Chul Woo Ahn, Bong Soo Cha, Sung Kil Lim, Kyung Rae Kim, Hyun Chul Lee; J Korean Endocr Soc. 2003;18(4):414-419. Published online August 1, 2003

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Abstract PDF: Riedel's thyroiditis is a rare form of chronic thyroiditis, characterized by a fibroinflammatory process which partially destroys the thyroid, often involving surrounding tissues. The relationship of Riedel's thyroiditis to other forms of thyroiditis is not clear. A case of Riedel's thyroiditis in a 51-year-old female patient, admitted with a previous diagnosis of subacute thyroiditis, is reported. She was first diagnosed with subacute thyroiditis based on clinical manifestation and radiologic and laboratory results. She was treated with glucocorticoid for 8 weeks. The follow-up lasted for 12 months. However, three years later she underwent a thyroidectomy operation due to an enlargement of the thyroid nodule and suspicion of malignancy. Histopathologic examination confirmed that she had Riedel's Thyroiditis. Until now, few case of Riedel's thyroiditis in patients with a history of subacute thyroiditis have been reported in the literature. Although the etiology of Riedel's thyroiditis is unknown, it may develop in the course of subacute thyroiditis.

A Case of Severe Thyrotoxicosis Induced by Hydatidiform Mole.: Jae Hak Lee, Jong Kun Park, Soon Hyo Kwon, Ji Oh Mok, Ji Sung Yoon, Yeo Joo Kim, Hyung Kyu Park, Chul Hee Kim, Sang Jin Kim, Hae Hyeog Lee, Gye Hyun Nam, Gye Hyun Kwan, Eun Suk Ko, Dong Won Byun, Kyo Il Suh, Myung Hi Yoo; J Korean Endocr Soc. 2003;18(4):420-425. Published online August 1, 2003

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Abstract PDF: Human chorionic gonadotropin (HCG) is one of the glycoproteins families synthesized by the placenta, and consists of 2 noncovalently joined subunits, namely, alpha and beta. The alpha and beta-subunits have a structural homology with the alpha and beta-subunits of TSH and LH. The thyrotropic action of HCG results from its structural similarity to TSH, so beta-HCG can bind to the TSH receptor in the thyroid gland. A high level of HCG, accompanied by an increased thyroid hormone level, can be observed in gestational trophoblastic diseases (GTD), such as a hydatidiform mole or a choriocarcinoma. However, the clinical symptoms of hyperthyroidism in GTD are rarely observed. A 27-years-old woman, admitted due to an amenorrhea of 11 weeks duration, with thyrotoxic symptoms, such as weight loss, palpitation, sweating, tremor, heat intolerance and anxiety, was evaluated. Her serum free T4 level was 8 times higher than normal, and her serum beta-HCG level was over 1,000,000IU/L. She had a curettage operation, with the pathological findings of a complete hydatidiform mole. These thyrotoxic symptoms developed due to a hydatidiform mole, and were accompanied with a highly increased serum beta-HCG level. After evacuation of the molar tissue, the thyroid hormone and thyrotoxic symptoms normalized. Here, this case is reported, with brief review of the literature.

Original Article

A Case of Atypical McCune-Albright Syndrome Associated with Hyperthyroidism and Hypersecretion of Growth Hormone.: Moon Bin You, Ki Hoon Kang, Byung Soo Lee, Eun Ha Chae, Myung Chan Kim, Jae Il Jung, Sun Hee Park, Hyo Jin Lee, Seok Tae Jung; J Korean Endocr Soc. 2003;18(4):426-432. Published online August 1, 2003

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Abstract PDF: McCune-Albright syndrome is characterized by polyostotic fibrous dysplasia, Caf -au-lait pigmentation and precocious puberty or other endocrinopathy. It can be caused by substitution of His, Cys or Gly for Arg 201st amino acid of the Gs protein subunit. The case of a 32-year-old woman, with atypical McCune-Albright syndrome, is reported. She had no skin lesion or precocity puberty. The polyostotic fibrous dysplasia was examined by a simple radiological image and whole body scan. She developed hyperthyroidism, with a multinodular toxic goiter. No thyroid related autoantibodies were detected. The cause of hyperthyroidism was thought to be a non- autoimmune thyroid hyperfunction. The level of growth hormone was not suppressed by oral glucose load. After a bromocriptine suppression test, the level of growth hormone decreased. There was no mass in the pituitary gland on a sellar MRI. A case of atypical McCune-Albright syndrome, including hyperthyroidism and hypersecretion of growth hormone, is reported.

Case Report

Primary Hyperaldosteronism with Increased Plasma Renin Activity due to Secondary Hypertensive Renal Impairment.: Kang Woo Lee, Hyuk Sang Kwon, Dong Il Shin, Chee Ho Noh, Jung Min Lee, Jong Min Lee, Kun Ho Yoon, Bong Yun Cha, Kwang Woo Lee, Ho Young Son, Sung Koo Kang; J Korean Endocr Soc. 2003;18(4):433-438. Published online August 1, 2003

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Abstract PDF: An increased plasma aldosterone concentration, with suppressed plasma renin activity (PRA), is an abnormal finding in primary hyperaldosteronism. A suppressed PRA is caused by aldosterone- dependent sodium retention and extracellular volume expansion. A case of primary hyperaldosteronism, due to adenoma, with increased PRA, was observed. An adrenalectomy and intraoperative renal biopsy was performed. In our patient, histologically proven renal arteriosclerosis was the probable cause of the escape of the PRA from the suppression by an aldosterone-producing adenoma. Normal blood pressure was not attained after the adrenalectomy. However, the blood pressure was then controlled by small doses of antihypertensive drug before resection of the tumor. In this case, the patient was treated with spironolactone, but the blood pressure was not correctly controlled. After the adrenalectomy, the blood pressure was well controlled with smaller dose of calcium channel blockers. So, an early adrenalectomy may be beneficial as soon as the diagnosis of an aldosterone-producing adenoma is confirmed, even in patients with hypertensive nephrosclerosis.

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