Betacellulin (BTC) purified from mouse β cell tumor (βTC-3) is a new member of the epidermal growth factor (EGF) family which can bind receptor tyrosine kinase, EGF receptor (erbB1) and erbB4. It has been demonstrated that proBTC mRNA was abundantly expressed in human pancreas tissue, and that BTC converted amylase-secreting rat acinar cell line (AR42J) into insulin-secreting cells, suggesting that BTC might be important for the growth and/or differentiation of islet cells. However, the cell type producing BTC in the pancreas has not been clarified. In this study, we examined the localization of BTC in human pancreas and islet cell tumors. Immunohistochemistry using specific antibodies to human BTC revealed that this protein was produced in α cells and duct cells, and probably in β cells in normal adult pancreas. Furthermore, strong immunoreactivity to BTC was detected in primitive duct cells of the fetal pancreas, and both insulinoma and glucagonoma cells also showed positive immunoreactivity to BTC. EGF receptor (erbB1) and erbB4 were expressed mainly in islet and duct cells, and duct cells, respectively. These results demonstrate the localization of BTC and its receptors, and suggest that BTC may be one of the factors that have physiologically important roles such as growth and differentiation of islet cells in the human pancreas.

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2, 3, 7, 8-Tetrachlorodibenzo-p-dioxin (TCDD) has been suggested as a possibble etiologic factor for endometriosis, a condition in which endometrium-like tissues are present outside the uterus. The prevailing view pertaining to the origin of endometriotic cells is that they are from eutopic endometrial cells which regurgitate through fallopian tubes. In order to get insight into the possible involvement of TCDD in the pathogenesis of endometriosis, we suspected that TCDD may act differently on the endometrium with or without endometriosis. To address this, we examined the presence of messenger RNAs of arylhydrocarbon receptor (AhR), AhR nuclear translocator (Arnt) and two dioxin-responsive genes, cytochrome P-450 1B1 (CYP1B1) and downstream of tyrosine kinases (p62(dok)), in the endometrium of women with or without endometriosis using semi-quantitative reverse transcription-polymerase chain reaction. All the genes were expressed throughout the menstrual cycle. The expression level of p62(dok) was higher in the proliferative phase than in the secretory phase. In contrast, the expression levels of AhR, Arnt and CYP1B1 seemed to be constant during the cycle. In terms of the comparison between non-endometriosis and endometriosis group, the mRNA levels of AhR, Arnt, CYP1B1 and p62(dok) were essentially similar. Interestingly, AhR mRNA level was significantly lower in smokers than in non-smokers. Based on the regression analysis, significant linear and positive correlations were observed between AhR and Arnt mRNA levels, and between Arnt and p62(dok) mRNA levels. In summary, expression of AhR and dioxin-related genes in the endometrium did not differ in women with or without endometriosis.

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Bisphenol A (BPA), a monomer of plastic used in consumer products, is abundant in the environment and enters the body by ingestion or adsorption. We developed a cell based transcription assay system using a reporter gene under the transcriptional control of estrogen receptor α (ERα) as well as ERβ and performed chloramphenicol acetyltransferase (CAT) assay on HeLa cells transfected with either human ERα cDNA or ERβ cDNA to characterize the estrogenic effect of BPA. Estrogenic activity of BPA was detectable at a concentration of 10^-9M and the activity increased in a dose dependent manner between concentrations of 10^-9M and 10^-6M of BPA for both ERα and ERβ. The estrogenic activity of 17β-estradiol at a concentration of 10^-8M was almost compatible with that of BPA at the concentration of 10^-6M of BPA for ERα as well as Erβ. CAT activity was significantly decreased when cells expressing ERa were incubated with 10^-6M of BPA and 10^-8M of 17β-estradiol while the activity was essentially the same for ERβ in the same condition, indicating that BPA exhibits only agonistic action for ERβ whereas it has dual actions as an agonist and antagonist of estrogen for ERα. These results indicates that BPA exerts its effects in ER subtype specific way, thus suggesting that the mode of action of endocrine disruptors are more complex than thought.

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Constitutive nitric oxide synthase (NOS) is expressed in rat adenohypophysis and clonal GH₃ cells. The mechanisms of action of nitric oxide (NO) to inhibit hormone secretion and the possible role of (6R)-5, 6, 7, 8-tetrahydro-L-biopterin (THB) in the action of endogenous NO were studied in GH₃ cells. Inhibiting NOS with NG-nitro-L-arginine or trapping NO with oxyhemoglobin enhanced both the basal and TRH-stimulated rat GH release. Sodium nitroprusside did not further decrease either the basal or the TRH-stimulated GH secretion, suggesting that endogenous NO exerted the maximal inhibitory effect. Inhibition of de novo synthesis of THB increased GH secretion. A cyclic guanosine-monophosphate (cGMP) antagonist did not increase the basal GH secretion but enhanced TRH-induced GH release. These findings suggest that endogenous NO plays an inhibitory role on basal GH release and TRH-stimulated hormone release from GH₃ cells in an autocrine or paracrine fashion, at least partly, through a cGMP-dependent pathway. It is also suggested that endogenous THB plays a role in NO production and subsequent inhibition of hormone secretion in GH₃ cells.

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A 35-year-old hyperthyroid woman who developed nausea, vomiting, tachycardia, nystagmus and mental disturbance, was referred to our hospital with a suspected diagnosis of thyroid storm. However, the thyroid gland was only slightly palpable, bruits were not audible, and exophthalmos was not present. Serum levels of thyroid hormone were increased, but TSH receptor antibodies were negative. Echography and color flow doppler ultrasonography revealed a slightly enlarged thyroid gland and a slightly increased blood flow, both of which were much less milder than those expected for severe hyperthyroid Graves' disease. Under the diagnosis of hyperthyroidism due to gestational thyrotoxicosis associated with Wernicke encephalopathy, vitamin B1 was administered on the first day of admission. Her consciousness became nearly normal on the second day except for slight amnesia. Her right abducent nerve palsy rapidly improved, but horizontal and vertical nystagmus, diminished deep tendon reflexes and gait ataxia improved only gradually. MRI findings of the brain were compatible with acute Wernicke encephalopathy. We concluded that history taking and physical findings are important to make a differential diagnosis of gestational thyrotoxicosis with acute Wernicke encephalopathy from Graves' thyroid storm, and that Wernicke encephalopathy should be treated as soon as possible to improve the prognosis

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Poorly controlled type 2or non-insulin dependent diabetes mellitus (NIDDM) patients exhibit high bone turnover, which decelerate with treatment according to the degree of improvement in glycemic control. In adults, higher bone turnover results in rapid bone loss. Therefore, deceleration of bone turnover is beneficial for bone. Troglitazone (Tro), a new anti-diabetic drug, is a thiazolidinedione (TZD) which promotes adipocyte differentiation by activating peroxisome proliferator activated receptor γ (PPARγ). Because, in the bone marrow, adipocytes and osteoblasts originate in common mesenchymal stem cells that are also essential for osteoclastogenesis, TZDs may directly affect bone metabolism. Thus, we examined the effects of Tro on metabolic bone markers in type 2 DM patients. Tro (400mg/day) was administered to 33 type 2 DM patients for four weeks. The day before and four weeks after starting Tro, serum and urine samples were collected after overnight fasting. Metabolic bone markers and glycemic indices were assessed. As bone resorption markers, urinary free and total deoxypyridinoline as well as urinary collagen type I C-terminal telopeptide were measured; as bone formation markers, serum bone type and total alkaline phosphatase (BALP and ALP) levels along with osteocalcin (OC) were used. No significant changes in fasting plasma glucose or HbA1c levels were observed in our short-term treatment with Tro. All the bone resorption markers, BALP and ALP were significantly decreased. OC was not significantly changed. The discrepant changes of OC from all the other metabolic bone markers suggest limitation of the use of OC as a reliable bone formation marker in diabetics. Our results that Tro decreased metabolic bone markers before significantly improving glucose metabolism suggest that it has direct effects on bone and decreased bone turnover. TZDs may spare bone mass in NIDDM subjects through its dual effects on glucose and bone metabolism.

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We reported 2 diabetic patients with nephrotic syndrome due to advanced diabetic nephropathy complicated by non-autoimmune primary hypothyroidism. Hypothyroidism developed along with the anasarcous status. Histological examinations of the thyroid gland revealed almost normal thyroid follicles without lymphocytic infiltration. The amounts of thyroid hormone lost into the extravascular space such as in urine and ascites were not sufficient to cause hypothyroidism alone. Serum total iodine levels measured during the hypothyroidal state in both cases were definitely elevated, and the perchlorate discharge test of both cases showed positive discharge (24 and 34%, respectively). The thyroid functions normalized after iodine restriction in the first case and initiating hemodialysis in the second case, in parallel with normalization of serum total iodine levels. These findings suggest that impaired
renal handling of iodine resulting in elevation of serum iodine levels, rather than an autoimmune mechanism or extravascular hormone loss, played a principal role in the development of primary hypothyroidism found in these 2 patients, probably through a prolonged Wolff-Chaikoff effect.

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The MENI gene has recently been cloned as the gene responsible for multiple endocrine neoplasia type 1 (MEN1) and its germline mutations have been identified in a number of familial MEN1 patients. However, mutation-negative cases have also been reported in some MEN1 families. We report here a Japanese MEN1 family, including a proband with no evidence of MEN1 gene mutation. The proband (51 y.o., female) had three major MENI lesions, including primary hyperparathyroidism (HP), prolactinoma, and pancreatic tumor. Her father and brother had HP, and her daughter had both HP and prolactinoma. When we analyzed the proband for a germline mutation of the MEN1 gene, the direct sequencing analysis showed no mutation in the coding region, on the promoter, 5' and 3'' untranslated regions of the MEN1 gene. We next examined the loss of heterozygosity (LOH) in the proband's parathyroid tumors using two benign polymorphisms (C2249G in intron 1 and 2248del3 in exon 10) in the MEN1 gene to detect LOH. LOH was not found in any of the four separate regions of the tumor tissues.

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A 72-year-old woman was found to have massive bilateral adrenal masses on computed tomography and was diagnosed with 21-hydroxylase deficiency (21-OHD) based on endocrinological findings. Physical examination revealed no abnormalities except markedly short stature. She was diagnosed with 21-OHD because she had an elevated serum 17α-hydroxyprogesterone (17-OHP) level which significantly decreased in response to dexamethasone. Percutaneous CT-guided biopsy and later autopsy confirmed that the adrenal masses were due to adrenocortical hyperplasia. Analysis of the CYP21 gene revealed that the patient was a compound heterozygote for the Ile-172→Asn mutation in exon 4 and the 8-bp deletion in exon 3. Simple virilizing 21-OHD (SV) would be predicted from this genotype. She had few symptoms associated with 21-OHD except for markedly short stature, but the serum 17-OHP level was higher than that of typical nonclassical form of 21-OHD and near to that of typical SV. This finding was confirmed by analysis of the CYP21 gene. From these results, we report that when adrenal masses are incidentally detected, 21-OHD should be ruled out to avoid excessive examination and surgery on the suspicion of adrenal carcinoma.

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In the present study, we report a Thai female with a de novo mutation in thyroid hormone receptor-β (TRβ) gene causing resistance to thyroid hormone (RTH). The patient was a 19 year-old woman who presented with goiter for 1 year. Except for tachycardia she had no signs of thyrotoxicosis. Previously she was treated with propylthiouracil based on the diagnosis of thyrotoxicosis for 9 months and her goiter became more enlarged. The patient was the only child of the family. Her parents were alive and healthy, and did not have goiter or any other thyroid diseases. Physical examination revealed no sign of thyrotoxicosis. Her thyroid gland was diffusely enlarged with an estimated weight of 100gm. Laboratory determinations revealed elevated free T4, T3 and nonsuppressed TSH levels. Exon 9 of the TRβ gene was amplified by PCR and the DNA sequence was determined by dye terminator cycle sequencing. Heterozygous point mutation in which T was replaced by C was detected at position 1274 (TTG to TCG) corresponding to a leucine to serine substitution at codon 330. No mutation was found in the parents indicating that the mutation was de novo. The nucleotide change created a restriction site for Taq 1 restriction endonuclease and the mutation was confirmed by restriction fragments length polymorphism. The same nucleotide change has been reported in a family with RTH.

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The present study was aimed to examine the possible functional relationship between melatonin and hypothalamic transmitters, endogenous opioids and excitatory amino acids in controlling gonadotropin secretion in ovariectomized estrogen-primed rats. An intravenous injection of naloxone (μ opioid receptor antagonist), N-methyl-D-aspartate (NMDA; NMDA receptor agonist) or luteinizing hormone-releasing hormone (LHRH) significantly elevated serum luteinizing hormone (LH) concentrations within 10min. An intraventricular treatment with melatonin, which did not affect the basal LH concentration by itself, significantly suppressed the effect of naloxone. However, the same melatonin treatment did not inhibit the NMDA-induced or LHRH-induced LH secretion. These results support the hypothesis that melatonin has a suprapituitary site of action to inhibit LHRH release, and suggest that the site of its action may be located downstream to that of naloxone action and upstream to that of NMDA in the hypothalamic LHRH neuronal pathway.

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