We compared immunoglobulin G (IgG) preparations obtained from untreated Graves' patients with those from Graves' patients in remission and normal subjects in terms of their activity to stimulate the phospholipase C-Ca²⁺ signaling. Ca²⁺ mobilizing activity of the untreated Graves' IgG preparations in FRTL-5 thyroid cells was statistically (P<0.01) and significantly higher than the activity of normal IgG preparations, whereas there was no significant difference in the activity between the remission Graves' and normal IgG preparations. Digital video imaging of fura2-loaded FRTL-5 cells confirmed that the Ca²⁺ mobilizing action of the untreated Graves' IgG preparations is an intracellular event. Phospholipase C activation by the untreated but not remission Graves' IgG preparations was statistically higher than that by normal IgG preparations. Involvement of the phospholipase C activation in the Ca²⁺ response mechanism was confirmed by the enhancement of the Ca²⁺ response by an adenosine derivative, N⁶(L-2-phenylisopropyl)adenosine (PIA) which can potentiate agonist-induced phospholipase C activation but not the Ca²⁺ mobilization itself. The Ca²⁺ response to the IgG preparations did not show a significant correlation with their cAMP response (TSAb). Therefore, the Ca²⁺ response to Graves' IgG preparations may be utilized as a functional marker for Graves' disease in addition to TSAb.

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We investigated the effects of simvastatin on the number and composition of apoproteinB (apoB)-containing lipoproteins in thirteen patients with hypercholesterolemia type IIa or IIb by measuring apoB by a highly sensitive latex method. Patients received simvastatin 5-10mg (7.7±0.7mg, mean±SEM) daily for 83-218 days (131±13 days). In both types of patients, treatment with simvastatin significantly reduced plasma cholesterol levels (mean±SEM mg/dl: in type ha from 234.4±5.4 to 171.4 ±7.8, in type IIb from 242.4±11.6 to 178.8±9.6), low density lipoprotein (LDL) cholesterol levels (from 122.6±5.2 to 68.5±4.6, and from 115.6±14.0 to 70.4±11.6 in the two types, respectively) and LDL apoB levels (from 94.5±6.6 to 60.6±7.0, and from 85.0±8.4 to 56.6±6.2, respectively). There was no significant change in cholesterol, triglyceride (TG) or apoB in very low density lipoprotein (VLDL). High density lipoprotein (HDL) cholesterol did not change in this study. With respect to lipoprotein composition, the ratio of either cholesterol or TG to apoB in VLDL, intermediate density lipoprotein (IDL) and LDL did not change significantly, but that of TG to apoB in the IDL fraction increased in type IIa. Simvastatin promotes more effective reduction in cholesterol and apoB in LDL than in VLDL, probably by increasing the hepatic LDL receptor which preferentially binds LDL.

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A large amount of LH/hCG treatment given to male rats is known to suppress the enzyme activity of cytochrome P450_c17 in Leydig cells for 48h. A high dose LH/hCG injection is also known to allow immunocytes, such as macrophages, to migrate into the testicular interstitial compartment. It has not been known, however, whether these cells play a role in that suppression. In this study, we examined if splenic macrophages have any effects on testosterone secretion from Leydig cells by culturing rat testicular interstitial cells (TIC). Splenic macrophages coultured with TIC significantly suppressed testosterone secretion. Macrophages co-cultured reduced both progesterone to testosterone conversion and the amount of cytochrome P450_c17 mRNA. The conditioned medium (SMCM), prepared by culturing macrophages for 12h, significantly reduced either testosterone secretion from TIC or progesterone to testosterone conversion by TIC. These results indicate that splenic macrophages suppress testosterone secretion from Leydig cells by suppressing the cytochrome P450_c17 enzyme in vitro, and that this effect is mediated at least in part by some soluble factors secreted from macrophages. Splenic macrophages migrating into the testis after LH/hCG stimulation could play a role in suppressing cytochrome P450_c17 in Leydig cells.

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Plasma free T4 (FT4) concentrations could be increased during hemodialysis in patients with chronic renal failure (CRF) because an increase in non-esterified fatty acids (NEFA) could interfere with the binding of T4 to thyroxine-binding globulin. To evaluate the effect of hemodialysis on the FT4 concentration in patients with CRF, we measured the FT4 in 39 patients with CRF by four assay methods including equilibrium dialysis, the ¹²⁵I-T4 analog method and enzyme immunoassay. The addition of the fatty acid sodium oleate to normal pooled sera led to a marked increase in FT4 as measured by equilibrium dialysis (Model FT4). A moderate increase in the serum FT4 concentration also was observed with an IMX enzyme immunoassay kit, whereas the Coat-A-Count analog method demonstrated no interference by sodium oleate. The mean serum FT4 prior to hemodialysis measured by equilibrium dialysis did not differ significantly from that in the normal control, although those measured by analog methods (Coat-A-Count and Amerlex) and IMX were subnormal. The FT4 by IMX were albumin-dependent, and the values decreased as the samples were serially diluted, but Model FT4 was not affected by the albumin level or the serial dilution. FT4 by Model FT4 showed a marked increase beginning 10min after the start of dialysis, and it correlated well with the plasma concentration of NEFA and the NEFA/albumin molar ratio. The other three assay methods, including one which is not affected by NEFA, did not show a change in FT4 at 10min, but a significant increase of 11 to 17% was observed by the end of dialysis. The TSH concentration decreased significantly during hemodialysis. These data suggest that (1) the low serum FT4 in hemodialysis patients measured by some immunoassay methods may be an underestimation due to the low albumin level; (2) FT4 actually increases during hemodialysis due to the actual increase in NEFA, although the marked increase in FT4 during hemodialysis as measured by equilibrium dialysis is an overestimation due to the in vitro generation of NEFA; and (3) one should beware of abberations in thyroid hormone parameters during hemodialysis and potential complications.

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Schmidt syndrome consists of adrenal insufficiency and Hashimoto's thyroiditis, which are probably caused by an autoimmune process. We encountered a patient who manifested severe generalized fatigue due to Schmidt syndrome recurrently. The endocrinological examination tests on the patient showed that the increase in thyroid stimulating hormone (TSH) and ACTH concentrations were not remarkable, despite hypo-function of the peripheral glands. Subsequent cranial magnetic resonance imaging (MRI) exhibited the existence of a pituitary tumor. The pathological findings on the resected tumor and endocrinological stimulation tests proved that the tumor was a FSH-producing adenoma. Although involvement of the pituitary region in Schmidt syndrome on rare occasions presents as hypophysitis, no pituitary adenoma has previously been reported in association with this syndrome. We present a patient with Schmidt syndrome and an accompanying FSH-producing pituitary adenoma. The coexistence of these disorders suggests that the functioning pituitary tumor might be considered as a pituitary lesion in Schmidt syndrome.

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We describe a 60-year-old man with a history of Tolosa-Hunt syndrome associated with intermittent painful ophthalmoplegia and a visual disturbance on the left side, who presented with signs and symptoms of severe hypoadrenalism and diabetes insipidus. Magnetic resonance imaging demonstrated enlargement of the hypophysis and infundibulum and left cavernous sinus. An endocrinologic study revealed anterior pituitary dysfunction and diabetes insipidus. The patient underwent a transsphenoidal biopsy which revealed chronic inflammation in the hypophysis, mucosa of the sphenoid sinus, and dura mater. The patient was treated with steroids that decreased the size of the hypophysis and infundibulum, but the symptoms of anterior pituitary insufficiency and diabetes insipidus have persisted. The chronic inflammation of the hypophysis and infundibulum is thought to have spread from the cavernous sinus.

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Hypertension and norepinephrine hypersecretion in a 59-year-old woman suffering from malignant pheochromocytoma with multiple metastases were appropriately controlled with α- and β- blockers, and α-methyltyrosine (α-MT), a catecholamine-synthesis inhibitor. Metastasized vertebrae were treated with external radiation to relieve pain, but this treatment had to be interrupted at a total dose of 20Gy because the patient suffered acutely exacerbated hypertension (200/110mmHg), tachycardia (160beats/min) and a low-grade fever. Simultaneously her serum levels of LDH, potassium, urea nitrogen, creatinine, white blood cell count, CRP and norepinephrine were significantly increased, suggesting that this episode was due to radiation-induced tissue destruction and the leakage of catecholamines and possibly interleukin-6, a cytokine mediating inflammation which is reportedly present in pheochromocytoma. The marked hypertension was controlled by continuous iv administration of phentolamine and propranolol. Athough radiation therapy effectively relieves pain due to neoplasmic metastasis to the bone, physicians should be aware that life-threatening complications such as the above occur in malignant pheochromocytoma. Sufficient pretreatment with adrenergic blocking agents and/or α-MT and careful monitoring of the patient's general condition during radiation therapy, even at a low dose, are highly recommended.

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Increased circulating soluble ICAM-1 (sICAM-1) levels has been previously reported in Graves' disease (GD) patients with or without ophthalmopathy (GO) and in patients with toxic nodular goiter but not in patients with subacute thyroiditis. Conflicting results have also been reported about the usefulness of sICAM-1 levels as a marker for the activity of hyperthyroidism. We have therefore determined sICAM-1 levels by a sandwich enzyme linked immunosorbent assay (ELISA) method in 10 patients with subacute thyroiditis (Group 1), who are at the initial or acute phase of thyroiditis, in 10 hypothyroidic patients with Hashimoto's thyroiditis (Group 2), in 10 patients with euthyroid nodular goiter (Group 3), in 10 patients with untreated GD patients with active ophthalmopathy (Group 4), in 10 hyperthyroid GD patients without clinical ophthalmopathy (Group 5), in 10 patients with GO who are euthyroid and treated with glucocorticoids for 3 months (Group 6) and in 20 normal subjects (Control Group). Groups 1, 2, 4, 5 and 6 (P<0.00001 for Groups 1, 4, 5, 6 and P<0.05 for Group 2) but not Group 3 showed increased sICAM-1 levels compared with the control group. However Groups 4 and 6 (patient with GO) showed significantly higher sICAM-1 levels (P=0.0003 for Group 4 and P=0.00013 for Group 6) than Group 5. Furthermore Group 4 showed slightly but not significantly higher sICAM-1 levels than Group 6. Mean sICAM levels were significantly decreased 3 months after glucocorticoid treatment (Group 6), but had not returned to normal levels. Three patients did not respond to steroid therapy and their sICAM-1 levels were not decreased. We concluded that patients with GO with or without hyperthyroidism and patients with subacute thyroiditis have elevated sICAM-1 levels. Moreover, sICAM-1 levels reflect the degree of inflammatory activity in the thyroid gland or orbital tissue independent of the thyroidal status, since we found elevated levels in both hyperthyroidism and hypothyroidism.

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To examine the autocrine/paracrine effect of parathyroid hormone-related peptide (PTHrP) on osteoblast function, the entire coding region of rat PTHrP (1-141) cDNA inserted into the expression vector was stably transfected into the rat clonal strain of the osteoblast-like cell, ROS 17/2.8, and established stable transfectants. Using the PTHrP-overexpressing ROS cells (ROS/PLP/6), we analyzed in vitro cell characterization and in vivo osteogenic properties. As expected, overexpression of endogenous PTHrP in vitro induced PTH/PTHrP receptor down-regulation confirmed by Northern blots, receptor binding assays, and functional analysis. The established transfectants indicated a decreased growth rate compared with the original non-transfected ROS 17/2.8. Although cAMP production induced by exogenous PTH was suppressed in ROS/PLP/6, the stimulatory effects of forskolin and chorela toxin showed no significant difference between the original ROS 17/2.8 and transfected cells, but the in vivo osteogenic properties were histologically potentiated in transfectants with increased bone matrix and acceleration of mineralization within tumors. The levels of osteocalcin and osteopontin mRNAs were also increased in transfectants. The down-regulated in vitro PTH/PTHrP receptor mRNA was restored in in vivo tumor tissues. Our study provides clear evidence that the in vivo osteogenic function in ROS cells is potentiated by PTHrP, through an autocrine/paracrine mode of action.

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In order to examine the time-dependent expression of the PRL receptor (PRL-R) gene at lactogenesis, the level of PRL-R mRNA was determined following ovariectomy in pregnant mouse mammary gland. Following reverse transcription, the quantity of mRNA was measured by the competitive polymerase chain reaction. The casein (a 22000 molecular weight component) mRNA level was measured as a marker for milk synthesis. Following ovariectomy, the onset of abortion occurred mostly at 22-23h and the level of casein mRNA began to increase at 12h. The long and short forms of PRL-R mRNAs were detected in a molar ratio of 1:0.2 on day 12 of pregnancy. Eight h after ovariectomy, the long form of PRL-R mRNA began to increase, showing a bell-shaped profile with the highest peak at 16h. The short form of PRL-R mRNA was at low levels and remained constant. The levels of the long form of PRL-R mRNA decreased similarly in the presence and absence of foster pups from 24 to 48h. Conversely, casein mRNA were maintained at high levels by supplying foster pups. The level of the long form of PRL-R mRNA reached a maximum prior to abortion. The present experiments demonstrated that the acute expression of the PRL-R gene occurred in the mammary gland at lactogenesis.

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The effect of interferon-beta (IFN-β) on thyroid function was studied in patients with chronic hepatitis who had no preexisting thyroid disease. Eleven patients (9 males and 2 females) aged 20 to 65 years, with a mean age of 47.7±13.5 years, were treated with 6 million units of IFN-β intravenously every day for 8 weeks. During IFN-β administration (4th to 8th week of treatment), both serum free thyroxine (FT₄) and free triiodothyronine (FT₃) concentrations decreased significantly (P<0.0005 and P<0.05, respectively): FT₄, 1.37±0.17 to 1.09±0.12ng/dl, and FT₃, 3.71±0.45 to .28±0.34pg/ml. On the other hand, serum TSH increased significantly from a baseline of 1.70±0.82 to 3.34±1.98μU/ml during IFN-β administration (P<0.005). Four to eight weeks after cessation of treatment, the mean serum FT₄ concentration was similar to that during IFN-β administration (1.04±0.14ng/dl), but mean serum FT₃ and TSH concentrations returned to pre-treatment levels (FT₃, 3.57±0.42pg/ml and TSH, .60±0.84 μU/ml). Both reverse T₃ and thyroglobulin were essentially unchanged. Tests for anti-thyroglobulin and anti-microsomal antibodies were negative in all the patients. These results indicate that IFN-β may inhibit thyroid function in patients without preexisting thyroid disease irrespective of humoral immune responses.

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In order to clarify the mechanism of xylazine-induced GH release, we investigated the effects of atipamezole, a selective α₂-adrenergic antagonist, and somatostatin (SRIF) on xylazine-stimulated GH release in calves. Xylazine injection (0.30mg/kg BW, iv) induced a rapid increase in the GH concentration. When atipamezole was used in combination with xylazine, it blunted the increase in the plasma GH concentration induced by the xylazine injection. The GH levels at 15-50min after the simultaneous injection of xylazine and atipamezole were significantly (P<0.05) lower than the corresponding values in the animals given xylazine alone. The area under the GH response curve for 120min after the simultaneous injection of xylazine and atipamezole was significantly (P<0.05) smaller than that for the xylazine alone. A series of five intravenous injections of 1mg of SRIF at 10-min intervals also blunted xylazine-stimulated GH release. Atipamezole partially suppressed xylazine-induced hyperglycemia, but SRIF completely suppressed the hyperglycemia for the first 60min after the xylazine injection and the suppression by SRIF was stronger than that by atipamezole. On the other hand, both atipamezole and SRIF failed to blunt xylazine-induced hypoinsulinemia. The present results suggest that xylazine stimulates GH release via the α₂-adrenergic pathway in cattle, but the mechanism of xylazine-induced hyperglycemia remains to be determined.

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A female infant with partial androgen insensitivity (PAIS) was first seen at 4 months of age with slight virilization of the genitalia and externally palpable testes. Sex chromosome was 46, XY. She received left orchidectomy and exploratory laparotomy at 2yr of age. At exploratory laparotomy, neither a uterus nor fallopian tubes were found. The right testis was preserved by fixing it at the external inguinal ring expecting spontaneous pubertal maturation. After discharge, serum levels of LH, FSH, testosterone (T) and estradiol (E₂) were measured annually, and the steroid responses to hCG stimulation were examined every two yr. At the age of 10yr, she developed breasts and a very feminine body habitus. At 12yr, she received a clitoroplasty and right orchidectomy. The fibroblast cultures were made from the genital skin whereby androgen receptor (AR) binding was assessed by radioreceptor assay using ³H-DHT as the ligand, and thermoinstability of AR was noted despite normal maximum binding (B_max) and dissociation constant (Kd) at 22°C. But another binding experiment with ³H-Mibolerone resulted in the lack of receptor binding. AR gene analysis with direct sequencing of coding exons of the gene revealed no abnormality of the AR gene. 5α-reductase activity was normal. Aromatase activity appeared to be enhanced in the genital skin fibroblast (GSF) cells as well as in the testicular tissue. The results of these studies indicated that the patient had PATS with impaired AR functions and increased aromatase activity. After the discharge, the patient has maintained feminine phenotype, receiving estrogen therapy with mestranol 0.02mg/day po.

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Acromegaly is an uncommon disease due to excessive amounts of growth hormone. Benign and malignant tumors have been reported in acromegalic patients. A 41-year-old female patient who had been followed up because of acromegaly by the endocrinology department for two years, was admitted to the hematology department for the evaluation of pancytopenia and the related signs and symptoms. Dopamine agonists were being used till a diagnosis of 'acute promyelocytic leukemia' was made. Occurrence of 'acute promyelocytic leukemia' in the course of acromegaly may have been caused by excessive endogenous GH or may be a coincidental situation.

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We report a family with isolated hypoparathyroidism. The proband was a 24-year-old woman, who presented with paresthesia of both hands. She had a mild degree of extrapyramidal signs, such as rigidity and decrease in arm swinging. Laboratory examinations revealed low PTH levels, mild hypocalcemia and hyperphosphatemia in the proband, her father, a younger brother and a younger sister, whereas her mother had normal serum calcium, phosphorus and PTH levels. These results indicate that four members of the family were affected, suggesting autosomal dominant inheritance. Brain CT revealed calcification of basal ganglia in the proband, her father and a younger sister, but not in her younger brother. Serum PTH-related protein (PTHrP) levels were examined, and found to be slightly high only in the father of the proband.

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Adrenal glands may be involved during both acute and chronic tuberculosis. They are enlarged in acute pulmonary tuberculosis. We aimed to investigate the changes in adrenal size in acute pulmonary tuberculosis before and after therapy in a prospective study. Eleven hospitalized patients with newly diagnosed sputum positive pulmonary tuberculosis were studied. Basal cortisol levels were measured in the patients before and after the therapy. Cortisol levels were also measured 30 and 60min after Synacthen (250μg iv.) injection in the patients before the therapy. The size of the adrenal glands was measured by computerized tomography. The maximum width perpendicular to the long axis of the body of the gland, maximum width of the medial and lateral limbs and the length of the adrenals were measured. All measurements were done before and after the eight-month anti-tuberculosis therapy. All 11 patients had an intact adrenal cortisol reserve. Both the width and length of the right and left adrenal glands were significantly greater before the therapy than after the therapy. We conclude that adrenal enlargement demonstrated by computerized tomography in acute pulmonary tuberculosis is reduced after appropriate therapy.

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We describe a case of diabetes insipidus (DI) due to a pituitary tumor in a 33-year-old pregnant woman who developed a sudden onset of polyuria (over 8l/day) and polydipsia at 30 weeks of gestation. Her plasma concentration of vasopressin (AVP) was low compared with high serum osmolality (298mOsm/kg), and her urine output was well controlled by treatment with desmopressin acetate (DDAVP). Cranial magnetic resonance imaging (MRI) demonstrated a 1.8×1.2-cm pituitary tumor, but she did not have any disturbance in the release of anterior pituitary hormones. The serum concentration of cystine aminopeptidase (CAP) was within the normal range for a woman at 34 weeks of gestation. After an uncomplicated delivery of a healthy girl, her polyuria gradually resolved. The size of the pituitary tumor gradually decreased in parallel to a reduction in her urine output, but a silent hemorrhage was detected in her pituitary gland 4 weeks after the delivery. Although pregnancy is sometimes associated with central DI, the occurrence of DI due to pituitary tumor under pregnancy is rare. The basal AVP recovered to within the normal range, but the low response of AVP secretion to high osmolality persisted. In this case, pregnancy may affect the manifestation of subclinical DI. This case may therefore enhance our understanding of the mechanisms of DI during pregnancy.

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Equine chorionic gonadotropin (eCG) consists of highly glycosylated α- and β-subunits and belongs to the glycoprotein hormone family that includes LH and FSH. eCG is a unique member of the gonadotropin family because it elicits response characteristics of both FSH and LH in other species than the horse. To determine the biological role of the N-linked oligosaccharide at Asn 56 of the α-subunit and O-linked oligosaccharides at the carboxyl-terminal peptide (CTP) of the β-subunit, two mutant eCGs, in which Asn 56 of the α-subunit was replaced with Gln (eCGα56/β) or CTP was deleted (eCGα/β-CTP), were produced by site-directed mutagenesis and transfecting chinese hamster ovary (CHO-K1) cells. LH- and FSH-like activities were assayed in terms of testosterone production and aromatase activity in primary cultured rat Leydig cells and granulosa cells, respectively. The wild type eCG showed similar LH- and FSH-like activities to native eCG in the in vitro bioassays. The LH-like activity of eCGα56/β was greatly reduced, whereas that of eCGα/β-CTP was unaffected, demonstrating that the oligosaccharide at Asn 56 of the α-subunit of eCG plays an indispensable role in LH-like activity. Interestingly, the FSH-like activity of Ecgα56/β was increased markedly in comparison with the wild type, and that of eCGα/β-CTP was also considerably increased. These data indicate that the dual activities of eCG, LH- and FSH-like activities, could be separated by removal of the N-linked oligosaccharide on the a-subunit Asn 56 or CTP-associated O-linked oligosaccharides.

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