Brain metastasis is an uncommon complication of differentiated thyroid carcinoma. Even more, cerebellar metastases from papillary thyroid carcinoma (PTC) are exceptional. We report a 69-year-old male patient with infiltrative PTC who developed high levels of thyroglobulin (Tg) and deteriorated neurological symptoms four years after the initial diagnosis. Computerized tomography (CT) of the brain demonstrated a cerebellar mass and the patient underwent surgery. Pathology revealed metastasis from PTC. Immunochemistry was positive for Tg. The patient had no other sites of distant metastases. Although PTC has generally a good prognosis, metastases to the cerebellum can occur, even as the first metastatic site, despite the fact that appropriate therapy (surgery, radioactive iodine therapy, TSH suppression therapy, chemotherapy and external radiotherapy) had been given for the primary tumour.

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Peripheral quantitative computed tomography (pQCT) is useful to measure volumetric bone mineral density (vBMD) distinguishing trabecular from cortical bones as well as quantity of bone geometry. In the present study, we examined the effects of age, grip strength and smoking on vBMD, bone geometry and bone strength index (polar strength strain index (SSIp)), and then compared with the differences between female and male by employing pQCT in Japanese 252 female and 230 male subjects. Age was negatively correlated with vBMD, cortical area (Ct.Ar) and cortical thickness (Ct.Th) as well as SSIp in both sexes, and the correlation coefficients were higher in female, compared with those in male. Although age was correlated with endocortical circumferences (En.Le) in both sexes, periosteal circumferences (Ex.Le) were correlated with age only in male. Volumetric BMD, Ct.Ar, Ct.Th and SSIp were significantly lower in the group with vertebral fractures, although En.Le and Ex.Le were similar between subjects with and without vertebral fractures. Grip strength was positively correlated with vBMD, Ct.Ar, Ct.Th as well as SSIp. The extent of correlation was much higher in female, compared with that in male. Ct.vBMD, Ct.Ar, Ct.Th and SSIp, but not trabecular vBMD, were significantly lower in the group with high Brinkman index (number of cigarettes smoked per day) × (duration of smoking (years)) in female. These parameters were not significantly different between groups with high and low Brinkman index in male. In conclusion, the present study demonstrated that age, grip strength and smoking affected forearm vBMD, bone geometry and bone strength index by pQCT. These effects were greater in female, compared with those in male.

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Biochemical markers of bone turnover have been suggested to be useful in monitoring the efficacy of antiresorptive therapy. In this study, we investigated the predictive value of bone turnover markers to determine short-term response in bone mineral density (BMD) and to identify nonresponders in 138 postmenopausal women (mean age 58 years) with osteoporosis given with either hormone thearpy (HT) or alendronate. Urinary type I collagen N-telopeptide (NTx) and serum osteocalcin (OC) at baseline, 3, and 6 months after treatment as well as spine and femoral neck BMD at baseline and 12 months were measured. Significant decreases in both NTx and OC were evident in women on treatment with antiresorptive agents as early as 3 months (p<0.01). Percent change of NTx at 3 months correlated with the percent change of spinal BMD at 12 months of treatment. When bone turnover markers were stratified by tertiles, the average rate of lumbar spine BMD gain increased significantly with increasing tertiles of baseline value (p<0.05) and percent change (p<0.05) of urinary NTx at 3 month of treatment. In terms of BMD response, urinary NTx at 3 months decreased significantly more in BMD responders group than in nonresponders group. Logistic regression analysis demonstrated that percent change of NTx at 3 months is an independent predictor to identify BMD nonresponders, defined as those whose BMD gain remained within the precision error range of dual energy X-ray absorptiometer (DXA). We conclude that biochemical markers of bone turnover, especially percent change in urinary NTx levels, can be used to determine BMD response to antiresorptive therapy in Korean postmenopausal women with osteoporosis.

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A 39-year-old woman who presented with typical Cushingoid appearance (moon facies, central obesity, purpura) was admitted to our hospital because of pulmonary infection. She was found to have hypertension, severe hypokalemia, and metabolic alkalosis. Endocrine data revealed elevated plasma levels of ACTH and cortisol with lack of circadian rhythm, non-suppressibility to high-dose dexamethasone, and hyperresponsiveness to CRH stimulation. Although no pituitary mass was detected by MRI of the brain, inferior petrosal sinus sampling showed a step-up of central to peripheral ACTH levels; these data are consistent with the diagnosis of Cushing's disease. She was successfully treated with metyrapone to control hypercortisolemia. Ten months later, a mass was detected in the ethmoid sinus, which was surgically removed. After resection of the ethmoid sinus tumor, her Cushingoid features and hypercortisolemia disappeared, but recurred after enlargement of a second mass in the maxillary sinus. After resection of the maxillary sinus tumor, her hypercortisolemia subsided. Histologically, the tumor tissues from both the ethmoid and maxillary sinus were identical and consistent with the diagnosis of olfactory neuroblastoma. Immunohistochemically, the immunoreactivities of ACTH and POMC were positive in the cytoplasm of tumor cells, and immunoreactive ACTH was demonstrated in both tumor tissues. Thus, this is the second rare case with ectopic ACTH syndrome caused by olfactory neuroblastoma thus far reported.

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In this retrospective longitudinal study, we focused on the clinical characteristics of Japanese individuals with recent onset impaired glucose tolerance (IGT) who have been followed up for insulin secretory function and 75-gram oral glucose tolerance test (OGTT) for more than 3 years annually before they progressed from normal glucose tolerance (NGT) to IGT. Subjects whose body weight did not show significant change for the period were selected and labeled as either NGT (no change in OGTT over 3 years) or IGT (progressors from NGT to IGT) groups (n = 24, each). We compared the basal biochemical data and response of plasma glucose and serum insulin after OGTT of the two groups. In the IGT progressors, significant increase of plasma glucose at 30 to 120 minutes during OGTT and significant decrease of HDL-cholesterol were observed since 3 years before onset of IGT. In addition to increase of serum glucose and decrease of HDL-cholesterol, serum insulin at 120 minutes during OGTT were significantly and remarkably high at onset and 3 years before onset of IGT. Plasma glucose at 30–120 minutes and serum insulin level at 120 minutes after glucose load are potentially significant predictors of progression from NGT to IGT even in subjects who do not show increase of body weight.

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Antipituitary antibody (APA) has been reported to be detected in patients with autoimmune thyroid disease. Type 2 iodothyronine deiodinase (D2) is expressed in both pituitary gland and thyroid gland. We studied the association of APA and D2 peptide antibody in patients with autoimmune thyroid disease. Rat pituitary gland homogenate and D2 peptide were used as antigens in the present study. APA and D2 peptide antibodies were measured by enzyme-linked immunosorbent assay (ELISA) in sera obtained from 42 patients with Hashimoto's disease, 26 patients with Graves' disease and 70 healthy control subjects. Moreover, D2 activity precipitation assay was performed in some patients with Hashimoto's disease. APA and D2 peptide antibody were elevated in patients with Hashimoto's disease and patients with Graves' disease, compared with control subjects. APA was positive in 32.4% (22/68), D2 peptide antibody was positive in 26.5% (18/68) of patients with autoimmune thyroid disease. APA was positive in 31.0% (13/42) of patients with Hashimoto's disease and 34.6% (9/26) of patients with Graves' disease. D2 peptide antibody was positive in 26.2% (11/42) of patients with Hashimoto's disease and 26.9% (7/26) of patients with Graves' disease. D2 peptide antibody was correlated with APA in patients with autoimmune thyroid disease. Moreover, precipitation of D2 activity was increased in some patients with Hashimoto's disease including a patient who also had idiopathic diabetes insipidus, and was correlated with D2 peptide antibody. These results suggest that D2 antibody may be associated with APA in patients with autoimmune thyroid disease.

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Bone is the second most frequent site of metastasis resulting from thyroid cancer. Many studies have investigated clinical features and prognostic factors of distant metastases stemming from thyroid cancer in Western countries. The purpose of this study was to review clinical characteristics of Korean patients with bone metastasis originating from thyroid cancer. Between January 1985 and August 2004, 28 patients with thyroid cancer were diagnosed with bone metastases at the Yonsei Severance Hospital in Seoul, Korea. Their clinical characteristics were analyzed retrospectively. Incidence of bone metastasis from follicular thyroid cancer was 6.8% (9 of 132 patients), and 0.4% (13 of 3,154 patients) from papillary thyroid cancer, with an odds ratio of 17.67 (95% confidence interval; 7.41–42). Twelve patients had no symptoms of bone metastasis. Overall mean number of metastasis sites was 2.6 ± 1.9, and 12 patients had a solitary bone metastasis. Survival rates between the synchronous and metachronous metastasis groups were not significantly different, and the number of metastasis sites did not affect survival. However, the survival of patients that underwent curative treatment was longer than those with palliation (P = 0.0317). In Korea, the overall incidence of bone metastasis resulting from thyroid cancer was less than our expectation. Many patients were asymptomatic, and had a tendency of undergoing less aggressive or palliative treatment, even though the long-term survival of distant metastasis resulting from thyroid cancer with active treatment is relatively good. Further studies of the prognostic factors and effectiveness of various treatments of these patients are needed to enhance survival.

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Growth hormone deficiency (GHD) is a risk factor for increased cardiovascular disease, and it has been recently demonstrated that abnormalities in coagulation system might contribute to the increased cardiovascular morbidity and mortality. However, there is not enough data related to the major thrombotic events in GH-deficient patients. We describe the case of a 62-year-old woman with Sheehan's syndrome who developed massive cardiac thrombosis. She was hospitalized with acute pulmonary edema. ECG revealed high ventricular responsive atrial fibrillation (AF) and T-wave inversion on precordial leads. The ejection fraction of left ventricle (LVEF) was measured as 60% by transthoracic echocardiography (TTE) and there was 2nd degree mitral regurgitation with concentric hypertrophic LV walls. Transesophagial echocardiography (TEE) established thrombi both at right atrium and left atrial appendix. Before anticoagulant therapy several hemostatic and fibrinolytic markers were measured. Except increased D-dimer concentration (763.14 μg/L (0–325)) we did not observe any pathological finding in these parameters. After 14 days of discharge, the patient was admitted to the intensive care unit with upper gastrointestinal bleeding. The warfarin and salicilate were stopped for two months. At the end of two months, the patient was again hospitalized with congestive heart failure and there was a high ventricular responsive AF on ECG. TEE was performed and three thrombi were demonstrated at right atrium (RA), left atrium (LA) and left ventricle (LV). There was no active bleeding on upper GIS endoscopy and anticoagulant therapy was restarted. In this particular case massive cardiac thrombi involving three chambers (LA, RA, LV) were more extensive than expected in AF. Moreover, there was a 2nd degree mitral regurgitation in the patient, and based on previous studies mitral regurgitation has been associated with less prevalent LA spontaneous echo contrast and fewer thromboembolic events. Therefore we hypothesized that severe GHD in the present case might be the major contributing factor in massive cardiac thrombosis. In summary, based on previous data there is increased risk of thromboembolic events in GHD although the mechanism is unclear yet. Our case is the first case showing massive cardiac thrombosis in a severe GH-deficient patient with Sheehan's syndrome. Therefore, patients with GHD should be screened carefully for thrombus in clinical practice, and further studies need to be done to understand the relation between GHD and coagulation system.

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The stress of direct laryngoscopy and passing an endotracheal tube through the vocal cords elicits haemodynamic, metabolic and hormonal changes such as raising blood catecholamine levels. Catecholamines are known stimulants of PTH secretion. The effect of tracheal intubation on plasma parathyroid hormone levels has not yet been investigated. We monitored changes in plasma parathyroid hormone levels before and after tracheal intubation in 72 hyperparathyroid patients undergoing elective parathyroidectomy for primary and secondary hyperparathyroidism. These findings were compared to data collected from 20 subjects who underwent elective surgery (thyroidectomy or laparoscopic cholecystectomy) under general anesthesia. In the control group, tracheal intubation significantly increased plasma parathyroid hormone levels from 59 ± 31 pg/ml to 91 ± 40 pg/ml (mean ± SD) (p<0.0003). In primary hyperparathyroid patients, the identical procedure increased plasma parathyroid hormone levels from 206 ± 104 pg/ml to 217 ± 113 pg/ml (p = 0.12) and from 898 ± 495 pg/ml to 1162 ± 613 pg/ml (p = 0.07) in secondary hyperparathyroidism patients. We concluded that tracheal intubation raises plasma parathyroid hormone levels. The mechanism underlying this response requires further investigation.

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Evaluation of adrenalectomy in patients diagnosed with ectopic ACTH syndrome was studied. Twenty-three clinical cases diagnosed with ectopic ACTH syndrome were analyzed at Chinese Academy of Medical Sciences and Peking Union Medical College Hospital (PUMCH). Cases consisted of 14 males and 9 females, with mean age of 38 years. All 23 cases had positive clinical, biochemical and radiology evidence for diagnosis of Cushing's syndrome. Sixteen of the 23 cases were treated with total adrenalectomy and the remaining 7 were treated without surgical intervention. Sixteen cases, having no identifiable source of ectopic hormone production, experienced resolution of presenting signs and symptoms after undergoing bilateral or unilateral total adrenalectomy; 1-year survival was 67%, 2-year survival 41% and 5-year survival 15%. In patients treated conservatively without surgical intervention, 1-year survival was 0%. In patients with no identifiable source of ectopic hormone production, bilateral adrenalectomy followed by hormone replacement treatment is effective.

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Dehydroepiandrosterone (DHEA), the most abundant human adrenal steroid, improves insulin sensitivity and obesity in human and model animals. In a previous study, we reported that orally administered DHEA suppresses the elevated activities of hepatic gluconeogenic enzymes like glucose-6-phosphatase (G6Pase) in C57BL/KsJ-db/db mice (Aoki K, Saito T, Satoh S, Mukasa K, Kaneshiro M, Kawasaki S, Okamura A, Sekihara H (1999) Diabetes 48: 1579–1585). However, the molecular mechanisms by which DHEA ameliorates insulin resistance are not clearly understood. In the present study, we cultured the human hepatoma cell line HepG2 with DHEA and measured the enzyme activity and protein expression of G6Pase to investigate the direct effect of DHEA on glucose metabolism in hepatocytes. DHEA significantly suppressed both the activity and protein expression of G6Pase. Moreover, DHEA decreased the gene expression of G6Pase and phosphoenolpyruvate carboxykinase, both of which were maximal at 1 μM DHEA, whereas the mRNA level of glucose-6-phosphate translocase was unchanged. Furthermore, DHEA enhanced 2-deoxyglucose uptake, although its effect was much smaller than that of insulin. These results suggest that DHEA may act at multiple steps in the regulation of glucose metabolism in the liver.

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Little is known about the immunosuppressive effect of glucocorticoids on TSH receptor antibodies. We observed the long-term prognosis and serum TSH binding inhibitor immunoglobulin (TBII) levels in patients with Graves' ophthalmopathy who had received intravenous methylprednisolone pulse therapy (pulse therapy) followed by oral prednisolone administration in order to ascertain how long the immunosuppressive effect of glucocorticoids continued. This is the first report on the effect of pulse therapy on Graves' disease outcome. We observed 67 patients who were treated by antithyroid drugs (ATD) alone for 2 years after pulse therapy. TBII was evaluated before and 3, 6, 12, 18, and 24 months after pulse therapy. The mean TBII decreased significantly 3 months after pulse therapy (p<0.001), and was maintained until 24 months. There were 24 patients whose TBII was positive (>15%) at 24 months, in whom the mean TBII decreased significantly 3 to 6 months after pulse therapy (p<0.001), but increased again at 12 to 24 months (p<0.05). Thus, the immunosuppressive effect of glucocorticoids may be lost at 12 months after pulse therapy in these patients. The remission rate in the pulse therapy group was 40.98%, and that of the control patient group was 48.57%. There was no significant difference between the two. These results suggest that the immunosuppressive effect of pulse therapy was temporary, and that pulse therapy did not increase remission rate of Graves' disease.

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Discrepancy of plasma ACTH levels measured by different immunoradiometric assays (IRMA) in a case with malignant gastric carcinoid causing ectopic ACTH syndrome was examined by gel chromatography and immunohistochemical analysis. A 49-year-old male was found to have a large gastric tumor, with muscle wasting, hypertension, diabetes and hypokalemia caused by hypercortisolemia. His plasma ACTH levels, although initially elevated, were found to be almost in normal ranges. The discrepancy of plasma ACTH levels was proven to be due to different IRMA kits used; the initial assay was performed by a kit that could recognize high-molecular weight (HMW) form as well as ACTH(1-39), but the later assay by another kit that could recognize only ACTH(1-39). Pathological examination of the gastric tumor was consistent with the diagnosis of malignant carcinoid. Immunohistochemical study revealed that immunoreactivity of proopiomelanocortin (POMC) was positive within the tumor cells, whereas those of ACTH and prohormone convertase 1/3 were negative. Molecular sieving analysis of patient's plasma by gel chromatography coupled with ACTH radioimmunoassay which could recognize HMW form and ACTH(1-39) and two different IRMAs revealed that the predominant form of ACTH was HMW form with a minor peak of ACTH(1-39). This is a rare case of ectopic ACTH syndrome caused by malignant gastric carcinoid with preferential production of HMW form of ACTH, possibly due to unprocessed POMC.

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Hypopituitarism is a well-known cause of secondary osteoporosis. However, patients receiving surgery for pituitary tumors or parasellar lesions have not been well studied for their bone sequel in Japan. We measured bone mineral density (BMD) and urinary type I collagen N-telopeptide (uNTX) in 35 postoperative patients including 25 with pituitary tumor (PT), 6 with craniopharyngioma (CP), and 4 others who had not been on sex hormone replacement, raloxifene, or bisphosphonate therapy. Compared with patients with PT, patients with CP had lower BMD and higher uNTX. Five out of 6 patients with CP had BMD lower than 80% of young adult mean (YAM), whereas 11 out of 22 patients with PT had BMD less than 80% of YAM. Patients with CP had significantly lower serum levels of gonadotropins, and they also tended to have lower serum levels of sex steroids, although statistically not significantly. Two postoperative patients with CP on sex steroid replacement, who were not included in the current analysis, had normal BMD. Of all the subjects, the prominent difference between patients with normal BMD and normal value of uNTX and patients with low BMD and elevated uNTX value was that the latter received higher dose of hydrocortisone replacement. The present study confirms postsurgical patients with pituitary or parasellar lesions, especially those with CP, are at high risk for osteopenia. In designing replacement therapy for those patients, it is important to consider bone by minimizing the dose of glucocorticoid, including sex steroids, and using other drugs that protect bone.

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We performed nationwide questionnaire-based surveys to characterize the current status of medical services for endocrine tumor syndromes, such as multiple endocrine neoplasia (MEN) and von Hippel-Lindau disease (VHL), in Japan. About 30% of the respondents had seen patients with either MEN or VHL, but the number of patients most of respondents had encountered was 5 or fewer. On the other hand, a large number of patients had been seen in a few hospitals, which seemed to be the result of the availability of specialists, rather than of geographic location. Although nearly 90% of hospitals had performed genetic tests, less than half of the hospitals had a clinical genetics division that provided genetic counseling to patients and/or family members. Not all of the respondents were thoroughly familiar with the "Guidelines for genetic testing" proposed by the consortium of Japanese genetic-medicine-related societies in 2003. Only 27.8% of respondents have read the guidelines and understood their concepts.

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The mechanisms of paradoxical TRH response in human somatotroph adenoma cells were investigated using intracellular calcium measurement and static incubation assay. Intracellular calcium measurement revealed that TRH induces a biphasic response: a transient increase followed by a sustained plateau. The transient phase was due to the calcium release from IP₃-regulated intracellular calcium store and the subsequent sustained phase was due to the calcium influx through the voltage-gated calcium channels. The signal transduction mechanism of the calcium plateau involved protein kinase C. These calcium responses, especially the second phase, was responsible for the TRH-induced GH release.

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The mechanism of adrenomedullin-induced prolactin release was investigated in prolactin-secreting human pituitary adenoma cells by intracellular calcium measurement and static incubation study. Adrenomedullin stimulated prolactin release in a concentration-dependent manner. The stimulation was dependent on extracellular sodium and voltage-gated calcium channels. PKA inhibitor attenuated adrenomedullin-induced prolactin release. The mechanism of adrenomedullin action was studied by fura 2-based intracellular calcium measurement. Adrenomedullin increased intracellular calcium concentration in these cells. The increase was dependent on extracellular sodium and voltage-gated calcium channels. PKA inhibitor attenuated the calcium response. These data indicate that adrenomedullin stimulates prolactin release by modulating calcium influx through voltage-gated calcium channels dependently on extracellular sodium. Mechanisms involving sodium-influx mediated depolarization may play a role in the stimulatory action.

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The mechanism of dopamine D₂ agonist-induced inhibition of GH secretion from GH-secreting adenoma cells was investigated by measurement of intracellular calcium concentration ([Ca²⁺] _i) and static incubation experiment. Bromocriptine decreased [Ca²⁺]_i in a concentration-dependent manner through D₂ receptor. The inhibition was abolished by pertussis toxin pretreatment. Bromocriptine did not decrease [Ca ²⁺]_i after nitrendipine had decreased it. 8Br-cAMP increased [Ca²⁺]_i but application of bromocriptine decreased it, suggesting that bromocriptine-induced inhibition of [Ca²⁺]_i is not dependent on bromocriptine-induced inhibition of adenylyl cyclase. Static incubation experiment revealed that bromocriptine inhibited GH secretion in a concentration-dependent manner. The inhibition was through D₂ receptor and was abolished by pertussis toxin pretreatment. 8Br-cAMP increased GH secretion. Bromocriptine decreased GH secretion even after 8Br-cAMP pretreatment. However, the GH release from cells incubated with bromocriptine alone was significantly less than that from cells incubated with bromocriptine after 8Br-cAMP pretreatment, suggesting a modulatory action of cAMP system in bromocriptine response.

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A common LH variant (V-LH) with Trp8Arg and Ile15Thr is often associated with ovarian dysfunction primarily in the Japanese population, and the LHB gene encoding V-LH is linked with a hyperfunctional promoter that could partly compensate for the somewhat weak biological effect of the V-LH in the Finnish and other several populations. We analyzed the promoter region in a Japanese infertile woman homozygous for the V-LH, to examine whether the hyperfunctional promoter is present or absent in the Japanese V-LH carriers with ovarian dysfunction. Direct sequencing was performed for a 661 bp promoter region from –8 to –668 bp of LHB, revealing homozygosity for eight nucleotide substitutions (–238A>G, –276G>A, –489C>A, –490T>A, –504T>A, –506T>C, –525T>G, and –552C>T) that are identical to those found in the hyperfunctional promoter. The results suggest that ovarian dysfunction frequently observed in the Japanese V-LH carriers would be due to some population-specific genetic and/or environmental factor(s) rather than to the lack of the hyperfunctional promoter and the resultant low biological effect of the V-LH. In addition, the tight linkage between the two missense substitutions in the coding region and the eight nucleotide substitutions in the promoter region of LHB appears to be common to various ethnic groups.

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A 56-year-old Japanese man was referred for examination of right adrenal tumor (3 cm). He had no apparent preexisting cancer by radiological workup and accordingly, the patient was considered as a nonfunctioning adrenocortical adenoma and scheduled for periodic CT scans every 6 months. However, five months after the initial diagnosis the patient complained of severe right back pain with remarkable enlargement of both adrenals (~20-fold volume). Although the origin of adrenal tumor was uncertain by pathological workup, positron emission tomography (PET) scan with ¹⁸F-2-fluoro-D-deoxyglucose (FDG) eventually revealed a hot spot on left upper lung, which was consistent with a lesion of thickened bulla wall observed by chest CT. The present case is a very rare example of abrupt enlargement of bilateral adrenals due to clinically isolated adrenal metastasis, suggesting the requirement of frequent observation with greatest care regarding morphologic changes of adrenal incidentalomas.

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