The steroidogenic activities in non-hyperfunctioning adrenal adenoma (NHFA) have not yet been fully examined. Steroid content both in adenoma and its non-tumorous adjacent adrenal tissue was measured by the HPLC system in 8 cases of NHFA and 2 cases of preclinical Cushing's syndrome (PCS). Activities of cytochrome P450c17α, P450c21, P450c11β, P450c18 and aldosterone-synthesizing enzyme (P450aldo) were also determined by the enzyme reconstitution system. Steroid content in NHFA varied but no significant difference was seen between NHFA and normal control adrenals. Activities of al lP450s except P450aldo were confirmed in NHFA, but they were almost equivalent to those in normal control adrenals. As no significant difference between NHFA and normal controls was observed in either steroid contents or P450s activities, the steroidogenic activity of NHFA is considered to be comparable to that of normal adrenals.

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We studied functional and histopathological changes in acromegalic cardiomyopathy following intermittent subcutaneous infusion of octreotide. A 68-year-old female patient with acromegaly associated with congestive heart failure due to dilated cardiomyopathy was initially treated with cardioactive medication for three months, but it was not effective in correcting echocardiographic abnormalities. Further treatment with intermittent subcutaneous infusion of octreotide (20μg/2 h) for 12 months not only reduced circulating GH and insulin-like growth factor-I (IGF-I) levels but also considerably improved histopathological changes in the myocardial specimen biopsied. These findings provide the first evidence of the favorable effect of octreotide on histopathological changes in acromegalic Cardiomyopathy.

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We examined the role of PKC in cortisol secretion from adrenocortical adenomas. Isolated cells were prepared from aldosterone producing adenoma (APA, n=5), APA complicated with preclinical Cushing's syndrome (APA+PC, n=1), PC (n=2), and cortisol producing adenoma (CPA, n=5). They were stimulated with 100nM ACTH, 1μM forskolin (FS), 1μM tetradecanoyl phorbol 13-acetate (TPA), and 100nM angiotensin II (AngII). ACTH was most potent to secret Cortisol. FS also stimulated cortisol secretion, but did less-potently. TPA and AngII also stimulated cortisol secretion significantly in cells from CPA. Furthermore, ACTH- and TPA-induced PKCα and β translocations from cytosol to membrane were observed in adenoma cells from APA+PC, PC, and CPA. In conclusion, it was suggested that ACTH-induced cortisol secretion may be mediated by both PKC and protein kinase A in adrenocortical adenomas, and that PKC-mediated signal transduction may be involved in ACTH-induced cortisol secretion in CPA.

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Leptin is the protein product of the ob gene, an adipocyte-specific gene, recently discovered in mice. Plasma leptin levels were determined in six normals, twenty-one subjects with impaired glucose tolerance, and forty-nine untreated NIDDM subjects. They increased with the augmentation of obesity (body mass index, BMI kg/m²) and were higher in females than in males: in BMI less than 25kg/m² the values of plasma leptin were 2.24±0.25ng/ml (n=29) in males and 3.01 0.39ng/ml (n=13) in females (P<0.054), respectively, in BMI between 25kg/m² and 30kg/m² they were 3.14±0.31ng/ml (n=10) in males and 10.66±2.86ng/ml (n=7) in females (P<0.0018) and in BMI higher than 30kg/m² their levels were 8.98±1.5ng/ml (n=11) and 11.74±2.2 ng/ml (n=6) (P<0.23), respectively. The severity of diabetes mellitus judged from the fasting plasma glucose level had no influence on the plasma leptin levels during OGTT, but the leptin levels decreased significantly during a tolerance test (P<0.001), and similar results were also seen during a breakfast test. The fasting plasma leptin in the male with FBS less than 140mg/dl had a significant correlation with the fasting plasma IRI level, but this correlation disappeared after taking obesity into consideration. Thus the plasma leptin was chiefly dependent on the body weight and gender and had no special relation to diabetic severity.

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To further understand a receptor-mediated apoptosis in rat thymus, we undertook experiments to examine the relationship between the induction of genomic DNA fragmentation and the depletion and the replenishment of cytosolic glucocorticoid receptor in rat thymus. Following administration of dexamethasone and prednisolone which had been known as synthetic glucocorticoids with different biological activities, we observed the fragmentation of thymus DNA in a dose-dependent manner. The time course and the extent of DNA fragmentation induced by these glucocorticoids were closely related to the degree of receptor depletion and the length of the depletion period. Relative biopotencies of dexamethasone and prednisolone estimated by their abilities to induce the DNA fragmentation were approximately 50:1. Administration of dexamethasone in combination with 2- deoxy-D-glucose, a potent inhibitor of the glycolytic pathway, significantly decreased the ability of dexamethasone to induce the DNA fragmentation, suggesting that a receptor-mediated DNA fragmentation by glucocorticoids is an ATP-dependent process. As an attempt to elucidate the molecular mechanism of DNA fragmentation in vivo, we reconstituted a cell-free system of thymus nuclei and cytosol fraction. Using the thymus cytosol fraction from dexamethasone-treated rats, we demonstrated for the first time an ATP-dependent fragmentation of nuclear DNA into nucleosomal units in vitro. Toward further understanding of the biochemical process of glucocorticoid-induced apoptotis in the thymocyte, the cell-free system reconstituted in the present study might provide a useful model system.

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We evaluated the usefulness of a desmopressin (DDAVP) test in the diagnosis of ACTH- dependent Cushing's syndrome. After an intravenous injection of 5μg DDAVP, plasma ACTH levels increased to more than 200% of the basal levels in 10 of 10 patients with Cushing's disease, but remained less than 150% in all of 11 normal subjects, 3 patients with Addison's disease, 5 cases of Cushing's disease in remission, and 3 patients with ectopic ACTH syndrome. Peak levels of plasma cortisol after the DDAVP stimulation were 159±14% in the patients with Cushing's disease, and less than 150% of the basal levels in the other 5 groups. We also found a case of Cushing's disease with periodicity which responded to DDAVP only in the active stage. In vitro studies revealed that DDAVP directly stimulates ACTH release from corticotropic adenoma cells through V1b but not V2 vasopressin receptors. In conclusion, the DDAVP stimulation test, i.e., determination of plasma ACTH levels after 55μg DDAVP injection, seems useful for discriminating Cushing's disease from normality, and may serve to facilitate the differentiation between Cushing's disease and ectopic ACTH syndrome.

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We describe an extremely rare case of thyroid carcinoma accompanied by sarcoid reaction in regional lymph nodes. The patient, a 40-year-old woman, was found to have anterior neck swelling during a routine medical examination. Physical examination revealed a bad movable and firm nodule measuring 3.5×2.5cm in the right thyroid lobe. Examination of a fine-needle aspiration cytology of the nodule suggested papillary carcinoma of class V. Right lobectomy and isthmectomy with neck dissection were performed. Histopathological examination of the resected specimens revealed papillary carcinoma accompanied by metastatic foci in right perithyroidal lymph nodes and non-caseous sarcoid- like granulomas in pretracheal, right upper internal deep cervical and submandibular lymph nodes. We concluded that these granulomas were due to a sarcoid reaction associated with thyroid carcinoma, after performing examinations to rule out the possibility of systemic sarcoidosis.

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Glucagon-like peptide-1(7-36)amide/(7-37)(GLP-1) is an incretin hormone which plays an important role in postprandial glucose homeostasis. Since GLP-1 potentiates glucose-induced insulin secretion, stimulates insulin biosynthesis and inhibits glucagon release, it is a potential tool for the treatment of diabetes mellitus. For this, an exact understanding of the structural/functional moieties of the peptide is mandatory. The present study investigates the importance of structural features of histidine⁷ at the N-terminus for GLP-1 action. Based upon binding and activity data obtained from ten different GLP-1 analogues we show that not the positive charge of the free α-amino group but the positive charge of the imidazole side chain of histidine is crucial for GLP-1 action. The presence of a ring structure and a basic function as well as the correct positioning of both seems to be decisive.

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The effects of mesenteric venous infusion of acetate, propionate and butyrate mixture (20.3, 40.5 and 81.0μmol kg^-1 min^-1 over 4h) on the secretion of GH was examined to investigate the effects of an increase in portal volatile fatty acids (VFA) on GH secretion in relation to inhibition of GH secretion after feeding in sheep. The mesenteric venous infusion at the rate of 40.5μmol kg^-1min^-1 increased the portal plasma VFA concentration within the approximate physiological range after feeding. Plasma GH was noticeably suppressed only at the infusion rate of 81.0μmol kg^-1 min^-1 and the change in the mean concentration from the base line was significantly less than in the control. Although GRF injection rapidly increased plasma GH, the change in the mean concentration from the base line tended to suppress only at the infusion rate of 81.0μmolkg^-1 min^-1. Plasma FFA was suppressed in a dose-dependent manner after VFA infusion. The change in the mean concentration from the base line was significantly suppressed only at the infusion rate of 81.0μmol kg^-1 min^-1 relative to the control infusion, but plasma glucose was unchanged by VFA infusion. It is concluded that because the increase in the portal plasma VFA concentration within the range of feeding did not suppress GH secretion, VFA absorbed by the digestive tract may not play a significant role in suppressing GH secretion after feeding in sheep.

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In this case report a patient with thyroid dysfunction who received chronic treatment with interferon-alpha (INF-α) following a diagnosis of chronic myelogenous leukemia (CML) is described. Generally INF-α induced dysthyroidism develops in the earlier phase of INF-α treatment. This is a case report of thyroid dysfunction which occurred 4 years after the patient began to receive INF-α administration. In addition, INF-α was administered to this patient for a longer period than those reported in the literature.

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It is known that prostate specific antigen (PSA) is strongly androgen dependent, but little is known about the effects of gonadotropin and testosterone treatments on the prostate and serum PSA levels in male hypogonadism. We have therefore determined serum PSA levels before and 3 months after treatment in 13 patients with idiopathic hypogonadotropic hypogonadism (IHH) and 14 patients with Klinefelter's syndrome. Plasma FSH, LH, testosterone, PRL, testis and prostate volumes were also determined before and 3 months after treatments. Patients with IHH were treated with hCG/hMG and patients with Klinefelter's syndrome received testosterone treatment. PSA levels were determined by a kinetic enzyme immunoassay method. In patients with Klinefelter's syndrome FSH and LH levels were significantly decreased but total and free testosterone and PSA levels were significantly increased after 3 months of treatment. Right and left testicular volumes were not significantly changed whereas prostate volumes were significantly increased after treatment. In this group PSA levels were significantly and positively correlated with the prostate volume both before (r=0.54, P=0.048) and after treatment (r=0.61, P=0.012). In the IHH group total and free testosterone and PSA levels were significantly increased after gonadotropin treatment but FSH and LH levels did not change significantly. Right and left testicular volumes and the prostate volumes were also significantly increased after 3 months of gonadotropin treatment. In this group PSA levels were correlated with prostate volume before (r=0.74, P=0.004) treatment but not after therapy (r=0.35, P=NS). Our results show that serum PSA levels increase after gonadotropin and testosterone treatment in male hypogonadism, but this could not be used as an index for the evaluation of the androgen action in the treatment of male hypogonadism, since PSA levels following treatments were correlated with the prostate volume or T levels only in patients with Klinefelter's syndrome but not in the IHH group.

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The effect of prolonged diabetes on epinephrine-induced adenosine 3', 5'-monophosphate (cAMP) response in the liver was examined in diabetes-prone BB/W rats. Basal and 1μM epinephrine- induced cAMP release from isolated perfused liver was similar in non-diabetic and diabetic BB/W rats with preserved adipose tissue. In adipose tissue-absent diabetic rats losing intra- and retro-peritoneal adipose tissue completely, both basal and 1μM epinephrine-induced cAMP release from the liver were enhanced (P<0.01, each case). Plasma epinephrine and norepinephrine were similar in non-diabetic, adipose tissue-preserved and -absent diabetic BB/W rats. The plasma free thyroxine level was similar in non-diabetic and adipose tissue-preserved diabetic BB/W rats, but was lower in adipose tissue-absent diabetic BB/W rats than in non-diabetic rats (P<0.01), but the frequency of lymphocytic thyroiditis was similar in these three groups, although plasma corticosterone was lower in adipose tissue-preserved diabetic BB/W rats (P<0.05) and the lowest in adipose tissue-absent diabetic BB/W rats (P<0.01). Lymphocytic infiltration was not observed in the adrenal or pituitary glands in any group. Plasma total protein and albumin were low in adipose tissue-absent diabetic BB/W rats (P<0.01, each case). In adipose tissue-absent diabetic BB/W rats, liver dysfunction and hepatomegaly, but no apparent histological change in the liver, were observed. Plasma glucose was higher (P<0.01) and plasma insulin lower (P<0.05) in adipose tissue-absent diabetic BB/W rats than in adipose tissue-preserved diabetic BB/ W rats. In conclusion, epinephrine-induced cAMP response in the liver was enhanced only in adipose tissue-absent diabetic BB/W rats. Denervation supersensitivity was not likely to be responsible for the enhanced β-adrenergic response. The observed reductions in plasma thyroxine and corticosterone seemed to result from severe diabetes. Although the severity of diabetes can vary continuously, severe diabetes with loss of adipose tissue appeared to cause significant changes in the metabolism and enhanced β-adrenergic response in the liver.

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Previously we reported an increase in bone resorption during pregnancy and lactation by measuring pyridinoline (Pyr) and deoxypyridinoline (D-Pyr). To further assess bone metabolism during peripuerperal periods, we measured the urinary excretions of C-telopeptide (CTX) and cross-linked N- telopeptide (NTX) of type I collagen, new markers of bone resorption. In addition to Pyr and D-Pyr, urinary CTX and NTX were measured by two ELISAs which recognize the corresponding peptide of type I collagen after urine samples were collected cross-sectionally from 230 women who consisted of 187 pregnants, 25 puerperants, and 18 age-matched nonpregnant women. Urinary CTX was also measured longitudinally from 10 pregnants at 5-9, 28-31 and 36-39 weeks of gestation and 1, 3, 6 months after parturition. Similar to the changes in Pyr and D-Pyr, the mean CTX and NTX values significantily increased in the 3rd trimester of pregnancy and remained high during puerperium compared with nonpregnant or early pregnant women (P<0.05). In a longitudinal study, the mean CTX value significantly increased in the 3rd trimester of pregnancy and at 1 month of puerperium compared with that in the early stage of pregnancy (P<0.05). These results further confirm our previous evidence that bone resorption is enhanced during the 3rd trimester of gestation and puerperium and suggest that urinary CTX and NTX measured by ELISA, which is more convenient than HPLC, are useful markers to assess bone resorption during peripuerperal periods.

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Our previous studies showed that endotoxin (Et) administration causes hypophosphaturia in the presence of PTH. In this study, we tested the hypothesis that enhanced renal nerve activity during endotoxemia is responsible for hypophosphaturia. Two weeks after bilateral renal denervation, phosphate excretion was examined in endotoxemic Wistar rats (300g body weight). Renal clearance studies were performed before and after 4mg/kg body weight Escherichia coli Et administration. Et administration resulted in a marked fall in glomerular filtration rates of innervated rats (n=12, from 2.09 ±0.11ml/min to 0.89±0.15ml/min, P<0.005) compared to saline-treated innervated rats (n=7, from 1.98 ±0.19ml/min to 1.76±0.16ml/min). The glomerular filtration rate of renal denervated rats was the same for saline-treated rats (n=9, from 2.67±0.92ml/min to 1.69±0.12ml/min) and Et-treated rats (n=10, from 2.37±0.19ml/min to 1.52±0.07ml/min). Fractional phosphate excretion was significantly reduced after Et challenge in innervated rats (from 24.0±3.3% to 11.8±2.2%, P<0.0001) compared to saline injection in innervated rats (from 26.9±3.9% to 33.0±1.6%). Although renal denervation improved the hypophosphaturia in comparison to the innervated rats, fractional phosphate excretion was still lower in Et-treated rats (from 28.8±5.0% to 18.0±4.7%, P<0.005) than in saline-treated rats (from 30.2±6.1% to 38.7±4.2%). In conclusion, our data did not support the hypothesis that renal nerves have an important role in reducing renal phosphate excretion during acute endotoxemia.

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Tamoxifen, a nonsteroidal estrogen antagonist, has been widely used in a hormonal treatment for breast cancer. The side effects of tamoxifen are generally recognized to be mild. However, we experienced three cases of severe hypertriglyceridemia and/or hyperglycemia induced by tamoxifen. For normalization of their hypertriglyceridemia we need to stop giving tamoxifen. In one of three cases we analyzed her lipoprotein profile in detail with lipoprotein lipase activities and apolipoprotein E phenotype. The case was a 49 year-old woman. After 15 months of tamoxifen administration, she was diagnosed as severe hypertriglyceridemia. Consecutively, severe hyperglycemia was occurred to need insulin therapy. After tamoxifen withdrawal, her triglyceride and glucose levels improved. Her lipolytic enzyme was reduced during tamoxifen treatment. Apolipoprotein E phenotype was uncommon E4/2. Although hypertriglyceridemia was not considered to be a risk factor for coronary heart disease, a marked hypertriglyceridemia might occasionally produce severe lethal pancreatitis. We recommend that a periodic plasma lipid analysis is needed for patients treated with tamoxifen, especially for diabetic and hypertriglyceridemic patients, to avoid such complications.

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We measured bone resorption markers in tumor patients with and without bone metastases and evaluated the diagnostic validity of these biochemical parameters in the diagnosis of neoplastic bone involvement. On the basis of radiography and bone scintigraphy findings, subjects were divided into 3 groups, 83 patients without bone metastases (META(-)), 22 patients with 1 or 2 bone metastases (META(+)) and 22 patients with more than 3 bone metastases (META(++)). Among the biochemical markers, urinary pyridinoline (PYR), circulating C-terminal telopeptide of type I collagen (ICTP) and urinary N-terminal telopeptide of type I collagen NTx were especially sensitive and specific and increased significantly not only in META(++) but also even in META(+). The efficacy of several bone metabolic markers in differentiating between patients with and without bone metastases was evaluated by receiver-operating characteristic (ROC) analysis, and PYR, ICTP and NTx were proved to have high diagnostic validity (area under the ROC curve; 0.75 for PYR, 0.77 for ICTP and 0.77 for NTx). Furthermore, their odds ratios showed significantly high values for both META(+) and META(++)(to META(++); 7.91 for PYR, 5.33 for ICTP and 5.70 for NTx). On the other hand, urinary deoxypyridinoline (DPYR) and serum total alkaline phosphatase (ALP) showed relatively low sensitivities, the odds ratio of ALP in particular being insignificant. In conclusion, several bone metabolic markers were proved to be useful in the diagnosis of bone metastases in patients with malignancies, particularly PYR, ICTP and NTx had rather high diagnostic validities among all markers examined in this study.

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Messenger RNA expression of activin β_C subunit in the liver was compared with that for β_A subunit before and after 70% hepatectomy. mRNA for β_C was abundantly expressed in the liver but decreased at 12h and later after 70% hepatectomy, whereas that for β_A was increased 12h after the hepatectomy. We also compared the expression of mRNA for β_A and β_C in cultured rat hepatocytes. mRNA for β_C subunit was abundantly expressed in the beginning of the culture but was reduced gradually after stimulation with epidermal growth factor. In contrast, mRNA for β_A subunit was undetectable before stimulation and was increased 24 to 48h after stimulation with the mitogen. These results indicate that expression of mRNA for β_C and β_A is regulated differently. The role of activin C may be different from that of activin A in the liver.

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