It appears that PACAP has a direct action on somatotrophs to releaase GH. The intracellular signal transduction mechanisms for PACAP might be similar to but partly distinct from those for GRH. PACAP might play a role in GH secretion induced by serotoninergic mechanisms but not in ultradian rhythm of GH secretion in the rat. PACAP can stimulate PRL release from the pituitary in rats possibly through indirect paracrine effect. In addition, PACAP might participate in regulation of PRL secretion via hypothalamic VIP.

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Growth hormone (GH) deficiency has been regarded as a principal determinant for growth failure following bone marrow transplantation (BMT). We herein analyzed final height and GH secretion in the patients who received BMT during childhood. The study on final height in 30 patients (23 males; 19 with malignant disease) who underwent BMT before or at the onset of puberty showed the following findings: (1) Final height SD score (SDS) significantly decreased compared to pretreatment height SDS. (2) Patients who underwent BMT before the age of 10 years showed significantly greater reduction in height SDS compared to those who received after the age of 10 years. (3) The type of disease or a difference in preconditioning regimen did not influence the outcome of growth. (4) No patient showed GH deficiency. The study on GH secretion included 71 patients who had been followed for more than 5 years and who underwent insulin tolerance test more than twice following BMT. Thirteen patients experienced poor GH response at least once. Two of these patients had poor GH response repeatedly. In conclusion, children who undergo BMT at younger age have a higher risk of growth failure, and GH deficiency is not a major contributing factor for growth impairment following BMT.

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A 45 year-old man had a typical episode of subacute thyroiditis with tender goiter, depressed radioiodine uptake (RAIU) and elevated erythrocyte edimentation rate. The titer of TSH binding inhibitor immunoglobulin (TBII), which had been 8.6% at initial presentation, rose to 14.9% in 2 weeks. TBII consisted of high titers (94%) of TSH stimulation-blocking antibodies (TBAb) and negative thyroid stimulating antibodies (TSAb). About 2 months after the first visit, TBII titers had risen to 48.9% and were persistently elevated for 5 months with high TBAb activity. The patient developed hypothyroidism with a maximum serum TSH level of 54.5μU/ml. TBII and TBAb titers then gradually decreased, and the patient spontaneously recovered from hypothyroidism. Eighteen months after the episode of subacute thyroiditis, he became hyperthyroid with elevated TSAb and negative TBAb values. Doppler ultrasonography showed increased blood flow in the thyroid, and RAIU at 24h was 53%. He was treated with antithyroid drugs, and soon became euthyroid. This case indicates that subacute thyroiditis can induce thyroid autoimmunity, and that the character of TSH receptor antibodies (TSHRAb) in these patients can change thereby modifying their thyroid function.

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Kallmann syndrome is defined by the association of hypogonadotropic hypogonadism and anosmia. The KAL1 gene is responsible for the X-linked form of Kallmann syndrome. We analyzed the KAL1 gene in 19 Japanese patients with Kallmann syndrome, including 3 patients reported previously, using PCR-direct sequencing method. All of 19 patients were sporadic, except for 2 monozygotic twins. In this study, there were 3 kinds of mutations in the KAL1 gene. One of them was a novel mutation consisting of a G to A substitution in the acceptor site at the junction of intron 6/exon 7. None of the mutations have been reported in countries other than Japan. In male sporadic patients with Kallmann syndrome, the incidence of mutations in Japanese patients (14%: 2 of 14 cases) was slightly higher than that in patients in USA (8%). Also, we found 2 polymorphisms, which were always found together in 6 patients.
The severity of hypogonadism was not related to the presence of mutations. Unilateral renal aplasia and mirror movement, which are frequently found in patients with the KAL1 gene mutation, were not related to the sites of mutations.

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Most pheochromocytomas can be cured by resection. In view of the unfavourable prognosis for surgical therapy in cases of late tumour detection and alignant tumours, the aim of the present study is to differentiate between typical signs and symptoms of malignant versus benign pheochromocytomas. We investigated the records of 133 patients retrospectively (1967-1998). In cases of benign tumours (104 of 133, mean age 42± 15.8 years) tumour size was 5.9±3.4cm, and history was 47.4±75.4 months. 7.7% of the tumours were extraadrenal, and 77% had paroxysmal manifestations. The other 29 patients (mean age: 39.2±21.9 years) had malignant lesions (tumour size: 9.4±5.9cm (p=0.0022); history: 7.4±5.6 months (p=0.0137); extraadrenal: 24.1% (p=0.0219); paroxysmal: 37.9% (p=0.0012)). Symptoms of patients with benign tumours were hypertension (80%), headaches (42.3%), sweating (30.8%), tachycardia (26%) and pallor (24% (Malignant: Hypertension 46%, p=0.0873; headaches 11%, p=0.0008; sweating 11%, p=0.0196; tachycardia 14%, p=0.1961 and pallor 0%, p=0.0010)). Abdominal pain and dorsalgia occurred more frequently in malignant pheochromocytomas (26% versus 7%, p=0.0014). Unusually short histories and extraadrenal localization appear to be suspicious for malignancy. The “typical” clinical signs and symptoms occur more frequently in patients with benign tumours and can therefore be regarded as typical signs of benign pheochromocytomas.

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The presence of keratinocyte growth factor (KGF) in human follicular fluid (FF) was investigated in a total of 145 FFs obtained during oocyte retrieval for in vitro fertilization (IVF) from 29 patients with no apparent endocrine disorders. The concentrations of KGF, estradiol, progesterone, testosterone and human chorionic gonadotropin (hCG) in FF were measured by enzyme-linked immunosorbent assay. FF samples contained relatively higher amounts of KGF (2194±87pg/ml), whereas its concentrations in serum were below assay limit (<31.2pg/ml). Concentrations of KGF in FF were positively correlated with both progesterone (r=0.311, p<0.0005) and testosterone (r=0.230, p<0.01) concentrations in FF. However, KGF concentrations were not ignificantly correlated with estradiol and hCG concentrations. KGF in FF was detected as a broad band (26-29kD) by immunoblotting, the size being reduced by 7kD after N-glycosidase treatment. In an in vitro experiment, KGF suppressed the basal and hCG-stimulated progesterone production by cultured human luteinized granulosa cells. In summary, we demonstrated the presence of KGF in human ovarian follicles, suggesting its possible role as a local
factor in regulating human ovarian functions.

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Adrenal incidentalomas have recently increased in incidence, and thus it has become important to establish clinical management of these patients. It is also important to evaluate whether these tumors are different from preclinical or overt Cushing's syndrome in their steroidogenesis. In this study, we therefore examined steroidogenesis of hormonally inactive adrenal incidentalomas via short-term culture of tumor specimens, in addition to animmunohistochemical study of steroidogenic enzymes. Five patients (two men and three women) diagnosed with adrenocortical incidentaloma without any clinical signs of adrenocortical hormonal excess except for hypertension and disturbed glucose tolerance, were recruited for this study. Hormonal findings, including circadian rhythms for cortisol and ACTH secretion, the response of ACTH to CRH infusion and results of dexamethasone suppression test were all within normal limits in these patients. Immunoreactivity for all steroidogenic enzymes involved in cortisol production was detected in tumor cells in all cases examined. Results of in vitro steroidogenesis analysis using short-term culture revealed that levels of cortisol secretion varied among the cases. There were no differences in the immunolocalization of steroidogenic enzymes and/or the levels of cortisol secretion between these hormonally inactive tumors and preclinical and/or overt Cushing's syndrome. Dehydroepiandrosterone-sulfotransferase (DHEA-ST) immunoreactivity in nonneoplastic regions was suppressed in one case in which the tumor secreted cortisol similar to preclinical and/or overt Cushing's syndrome. These results demonstrate that the levels of in vitro steroid production and/or the immunolocalization of steroidogenic enzymes in hormonally inactive drenocortical tumors vary markedly and are not overtly different from those of preclinical and/or overt Cushing's syndrome.

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We report a case of pulmonary metastatic thyroid carcinoma complicated with Graves' disease. A 56year-old Japanese woman was referred to the Niigata Cancer Center Hospital for isotope therapy for pulmonary metastatic thyroid carcinoma. In 1993, she received a left-hemithyroidectomy. In 1999, the remnant thyroid was resected for isotope therapy of metastatic lesions in the lungs. Although she had been receiving suppressive therapy with levothyroxine, her general condition was good, and TRAb was positive before the operation. After a total thyroidectomy, the patient became thyrotoxic. For functioning metastatic lesions, the patient was treated with 5550 MBq of ¹³¹I and methimazole. Thyroid function was normalized after the therapy but TRAb and TSAb levels remained high.

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A 65-year-old woman with Graves' disease presented marked diurnal changes in white blood cell (WBC) and granulocyte counts. Granulocyte count was low and sometimes decreased to 0.2-0.3×10⁹/l in the early morning and increased in the afternoon irrespective of her thyroid status. She did not develop sore throat or fever during the investigation period. The present study indicates that these unusual diurnal changes in WBC and granulocyte counts should be considered in the differential diagnosis of agranulocytosis in Graves' disease patients treated with an antithyroid drug.

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The aim of the present study was to investigate the prevalence of antipituitary antibodies (APA) in patients with autoimmune thyroid disease as determined by Western blot analysis and enzyme-linked immunosorbent assay (ELISA). Results by Western blot analysis showed positivity for APA in serum of 22.4% of patients with Graves' disease (n=143, p<0.05) and 18.5% of patients with Hashimoto's thyroiditis (n=54, p<0.05), which were significantly higher than 6.2% in healthy controls (n=97). Similar results were obtained with ELISA. The titers of APA measured by ELISA (APA/ELISA) remained unchanged before and after therapy with antithyroid drug for Graves' disease, while thyrotropin-binding inhibitor immunoglobulins (TBII) decreased ignificantly. Similarly, no changes in APA by Western blot analysis were observed after therapy. In patients with Graves' disease, APA were not associated with thyroid status. There was no difference in APA between patients with positive and negative thyroid autoantibodies. A significant but weak positive correlation between APA/ELISA and anti-human GH measured by ELISA (anti-hGH/ELISA) was observed in patients with Graves' disease (r=0.601 p<0.001) and Hashimoto's thyroiditis (r=0.428 p<0.005). These findings have demonstrated the existence of APA detected by Western blot analysis and ELISA in some cases of autoimmune thyroid disease. The present results suggest that hGH and other antigens may be involved in APA in patients with Graves' disease and Hashimoto's thyroiditis.

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The effects of heat exposure on the adrenergic modulation of pancreatic secretion were investigated. Five ewes fed at maintenance level (ME base) were housed in thermoneutral (TN; 20°C) and hot (30°C) environments. Heat exposure caused an increase in respiration rate and a slightly higher rectal temperature, and decreases in basal insulin and glucose concentrations. Infusions of saline plus epinephrine caused increases in glucagon and glucose concentrations, and no significant change in insulin secretion. Phentolamine (an adrenergic α-antagonist) plus epinephrine augmented insulin secretion; however, this insulin secretory response was inhibited by heat exposure. Propranolol (a β-antagonist) plus epinephrine produced a slight decrease in insulin secretion in the TN environment, whereas no effect was observed during heat exposure. While glucagon secretion through α-adrenergic stimulation was not affected by heat exposure, homeostatic signals controlling insulin release seemed to be affected during heat exposure. We thus hypothesised that insulin concentration is decreased in sheep fed at maintenance level in hot environments, and that this response is mediated in part by a modulation of β-adrenergic function.

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AIB1 (amplified in breast cancer 1) is a coactivator which stimulates the transcriptional activity of the liganded-estrogen receptor (ER). It has been reported that AIB1 gene is amplified and overexpressed in some breast cancer cell lines. AIB1 contains a stretch of homopolymeric glutamines (poly-Q). We reported that the poly-Q shows polymorphism, which provides an opportunity to study somatic gene alteration such as loss of heterozygosity (LOH). In the present study, we aimed to investigate the frequency of somatic gene alteration in Japanese patients with breast cancer. Amplification of AIB1 gene was detected only in 1 (2.6%) of 39 breast cancer tissues by DNA dot blot analysis. On the other hand, LOH was found in 2 (8%) breast cancer tissues out of 25 patients showing heterozygosity in peripheral blood mononuclear cells (PBMC). Taken together, both LOH and amplification of AIB1 gene were identified in breast cancer patients, raising the possibility that AIB1 have oncogenic as well as antioncogenic potential for the pathogenesis of breast cancer.

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New Zealand obese (NZO) mouse, a genetic model of obesity, shows hyperphagia, hyperinsulinemia and leptin resistance. We analyzed subcutaneous adipose tissue proteins in NZO mice with a two-dimensional gel electrophoresis technique followed by protein sequence analysis. NZO mice showed hyperinsulinemia and hyperleptinemia. Abdominal subcutaneous adipose tissue was inspected in NZO and C57BL/6J lean mice. Two-dimensional gel electrophoresis detected 4 spots which were obviously reduced in NZO mice. Those spots were p26, p19, p18 and p15. Internal sequences of the p26 and p15 protein were homologous with those of carbonic anhydrase III, p19 was cytochrome b5, p18 was superoxide dismutase. Serum arachidonic acid level in NZO mice was lower by 80% of C57BL/6J mice. The present study demonstrated the reduction of several enzymes related to lipid metabolism in NZO mice. These data raises the hypothesis that the supposed changes of membrane fluidity caused by altered membrane lipid content may involve central leptin resistance of this model of obesity.

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Although several authors have reported single cases illustrative of some ultrasonographic characteristic of parathyroid carcinoma, the value of ultrasonography for diagnosing this entity remains to be determined. The purpose of our study was to investigate the ultrasonographic features of parathyroid carcinoma in a large number of cases. We assessed the shape, contour, echogenicity, and depth-width (DW) ratio of 16 parathyroid carcinomas and 61 parathyroid adenomas. Ultrasonography showed that parathyroid carcinomas tend to be large, inhomogeneous, hypoechoic masses with lobulated contours. In contrast, parathyroid adenomas were small, homogeneous, hypoechoic masses with smooth borders. The mean (range) DW ratios for parathyroid carcinomas were 1.21 (0.91-2.5) and 0.64 (0.33-1.47) for adenomas; the difference was statistically significant (p<0.0001). The DW ratio was ≥1 in 15 (94%) of the 16 cases of carcinoma, whereas only 3(5%) of the 61 adenomas had a similar ratio. Ultrasonographic examination is useful not only for preoperative localization but also for differentiating parathyroid carcinoma from adenoma. Parathyroid tumors with irregular margins, inhomogeneous echogenicity, and a DW ratio ≥1 are likely to be malignant.

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We investigated menstrual cycle-dependent changes in the expression of PTHrP and PTH/PTHrP receptor in the human endometrium by immunohistochemistry, and competitive reverse transcription and polymerase chain reaction (RT-PCR). Human endometrial tissues were obtained from patients who underwent gynecological surgery due to cervical cancer (carcinoma in situ) or ovarian cancer. The mean age of the 20 patients was 36.5 (range 31-44) years. For analysis of mRNA expression, specimens from proliferative (mid, n=5; late, n=5) and secretory (early, n=4; mid, n=4) phases were used. Immunohistochemical expression of PTHrP and PTH/PTHrP receptor was observed in the cytoplasm of both epithelial and stromal cells. Stronger staining of PTHrP was found in glandular epithelial cells than in stromal cells. The staining during the proliferative phase was stronger than that in the secretory phase and the difference was particularly remarkable when comparing samples from the same patient. PTH/PTHrP receptor was also present in both epithelial and stromal cells of the endometrium. However, no difference was observed in receptor expression between the proliferative and secretory phases. Competitive RT-PCR revealed that the expression of PTHrP mRNA was higher during the proliferative phase than in the secretory phase, although no difference was observed in PTH/PTHrP receptor mRNA expression. The data suggest that endometrial proliferation may be mediated by a local PTHrP autocrine and/or paracrine mechanism.

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We report the case of a 31-year-old man with Graves' disease who manifested malignant hyperthermia during subtotal thyroidectomy. His past medical history and family history were unremarkable. Before surgery, his condition was well controlled with propylthiouracil, β-adrenergic blocker and iodine. During the operation, anesthesia was induced by intravenous injection of vecuronium and thiopental, followed by suxamethonium for endotracheal intubation. Anesthesia was maintained with nitrous oxide and sevoflurane. One hour after induction of anesthesia, his end tidal carbon dioxide concentration (ET_CO2) increased from 40 to 50mmHg, heart rate increased from 90 to 100 beats per min and body temperature began to rise at a rate of 0.3°C per 15min. Suspecting thyroid storm, propranolol 0.4mg and methylprednisolone 1, 500mg were administered, which, however, had little effect. Despite the lack of muscular rigidity, the diagnosis of malignant hyperthermia was made based on respiratory acidosis. Sevoflurane was discontinued and dantrolene was given by intravenous bolus. Soon after the treatment, ET_CO2, heart rate and body temperature started to fall to normal levels. His laboratory findings showed abnormally elevated serum creatine phosphokinase and myoglobin but normal thyroid hormone levels. Since dantrolene is efficacious in thyrotoxic crisis and malignant hyperthermia, an immediate intravenous administration of dantrolene should be considered when a hypermetabolic state occurs during anesthesia in surgical treatment for a patient with Graves' disease.

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We analyzed the disorder of water metabolism in a 32 year-old female with chronic hypernatremia. She had meningitis at 4 years, and ventriculo-peritoneal shunt operation at 13 years because of normal pressure ydrocephalus. At 14 years hypernatremia of 166mmol/l was initially found and thereafter hypernatremia ranging from 150 to 166mmol/l has been persisted for the last 18 years. Physical and laboratory findings did not show dehydration. Urine volume was 750-1700ml per day and urinary osmolality (Uosm) 446-984mmol/kg, suggesting no urinary concentrating defect. Plasma arginine vasopressin (AVP) levels ranged from 0.4 to 1.2 pmol/l despite hyperosmolality of 298 through 343mmol/kg under ad libitum water drinking. There was no correlation between plasma osmolality (Posm) and plasma AVP levels, but Uosm had a positive correlation with Posm (r=0.545, P<0.05). Hypertonic saline (5% NaCl) infusion after a water load increased Uosm from 377 to 679mmol/kg, and plasma AVP from 0.2 to 1.3pmol/l. There was a positive correlation between Posm and plasma AVP levels in the hypertonic saline test (r=0.612, P<0.05). In contrast, an acute water load (20ml/kg BW) verified the presence of impaired water excretion, as the percent excretion of the water load was only 8.5% and the minimal Uosm was as high as 710mmol/kg. Urinary excretion of aquaporin-2 remained low in concert with plasma AVP levels. No abnormality in pituitary-adrenocortical function was found. These results indicate that marked hypernatremia is derived from partial central diabetes insipidus and elevated threshold of thirst, and that enhanced renal water handling may contribute to maintenance of body water in the present subject.

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Although type 1 and type 2 diabetes are regarded as clinically distinct diseases, several lines of evidence have suggested common genetic factors between the two types of diabetes. The non-obese diabetic (NOD) mouse, an animal model of type 1 diabetes, and the Nagoya-Shibata-Yasuda (NSY) mouse, a model of type 2 diabetes, are derived from the same outbred colony, Jcl:ICR, suggesting a shared susceptibility between the two types of diabetes in mice. Genetic as well as functional studies have supported the possibility that Tcf2, which encodes the transcription factor, hepatocyte nuclear factor 1β (HNF-1β), is a candidate gene for the common susceptibility between NSY and NOD mice. Txn, encoding thioredoxin which is a redox (reduction/oxidation)-active protein, is also a positional and functional candidate for a common susceptibility gene. To investigate whether either of these two genes is a common susceptibility gene, the coding nucleotide sequences of these two genes were compared among the NSY, NOD and control C3H strains. The coding sequence of Tcf2 of the NOD mouse was identical to that of the C3H mouse, but was different from that of the NSY mouse. The coding sequence of Txn was identical in the three strains. These data suggest that neither of the two genes is a common susceptiblity gene between type 1 and type 2 diabetes in mice.

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Tumor necrosis factor-α (TNF-α) has been reported to inhibit adipocyte differentiation in which multiple transcription factors including CCAAT enhancer binding proteins (C/EBPs) and peroxisome proliferator-activated receptor (PPAR) γ play an important role. Induction of C/EBPα and PPARγ, which regulate the expression of many adipocyte-related genes, is dependent on the expression of C/EBPβ and C/EBPδ at the early phase of adipocyte differentiation. To elucidate the mechanism by which TNF-α inhibits adipocyte differentiation, we examined the effect of TNF-α on the expression of these transcription factors in mouse 3T3-L1 preadipocytes. TNF-α did not abrogate the induction of C/EBPβ and C/EBPδ in response to differentiation stimuli. In fully differentiated adipocytes, TNF-α rapidly induced C/EBPβ and C/EBPδ, whereas it downregulated the expression of C/EBPα and PPARγ. Our results suggest that TNF-α inhibits adipocyte differentiation independently of the downregulation of C/EBPβ and C/EBPδ.

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We report a rare case of Graves' disease associated with struma ovarii. A 26-year-old Japanese woman had preexisting Graves' disease and was positive for TSH receptor antibody. She had been on antithyroid medication at presentation. She noted a mass in the lower left abdomen, which was diagnosed as a left struma ovarii by radiological work-up including computed tomography, magnetic resonance imaging and scintigraphy. The surgically excised teratomatous tumor, containing cystic spaces with thyroid tissue, was histologically proved to be struma ovarii. Since thyroid function tests and TSH receptor antibody did not change after surgery, her hyperthyroidism was considered to be due to Graves' disease. Our case was diagnosed as struma ovarii before surgery using various imaging studies.

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A 66-year-old Japanese woman presenting with recent onset of type 1 diabetes mellitus and cerebellar ataxia was admitted to our hospital. Physical examination on admission revealed coordinate disturbance due to cerebellar ataxia, and the laboratory examination showed marked hyperglycemia with ketosis and impaired insulin secretion. Anti-glutamic acid decarboxylase (GAD) antibodies in high titer were detected in patient's serum. Immunoblotting showed the patient's serum reacted with a 65kDa protein in tissue extracts from rat pancreas and cerebellum, and immunohistochemical study produced positive immunostaining in the pancreatic islets of Langerhans, the axons of Purkinje cells and the nerve terminals in the granular layers of cerebellum of the rat. This is the first case presenting with concomitant type 1 diabetes and cerebellar ataxi associated with high titers of circulating anti-GAD antibodies which may play a critical role in the development of the diseases.

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The aim of the study is to determine the impact of Chlamydial seropositivity on atherosclerosis in a group of patient requiring coronary and/or carotid revascularization. A population of 30 diabetic patients (group 3) and 26 nondiabetic patients (group 2) with angiographically documented coronary and/or carotid artery disease were enrolled for the study. Volunteers from the relatives of hospital staff with no known disease (n=29; group 1) were included as the control group. Serum samples from the participants were assayed for cardiovascular risk factors including total serum cholesterol, triglyceride and lipoprotein levels, fibrinogen, Hb A1_c levels and IgG titers for Chlamydia pneumonia (C. pneumonia). Chlamydial seropositivity was analysed further to determine a possible impact on atherogenesis. Serum LDL cholesterol levels revealed statistically significant difference between groups 1 and 2 (p=0.001). There was no difference between groups 2 and 3 regarding LDL cholesterol levels. There was no significant difference among the groups with respect to C. pneumonia seropositivity and the other atherosclerotic risk factors. Chlamydial seropositivity was found to be more frequent in males than in females (p=0.008). In the C. pneumonia seropositive group, serum fibrinogen and lipoprotein a levels were found to be significantly higher than the seronegative group (p=0.0001 and p=0.001, respectively). Other atherogenic risk factors were similar in the seropositive and negative groups. The causal role of Chlamydial infections in atherosclerotic plaque formation might be due to their influence on the serum fibrinogen and lipoprotein a levels.

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