1) CRF within and beyond the neuroendocrine system may function in an integrated manner to effect adaptive responses to stress.
2) Mapping the localization of fos expression highlights CNS regions that probably participate in the mediation of stress and centrally administered CRF.
3) Although c-fos mRNA levels may serve as a postsynaptic marker of neuronal transcriptional activity, the relationship of Fos to products of genes activated later is unknown at present. Further studies will be needed to clarify the role of fos in the HPA axis.

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We report the case of 71-year-old male who was once diagnosed as having diabetic amyotrophy, because of pronounced wasting in proximal muscles, massive weight loss, and development of paresthesia in his legs. Afterwards, ragged red fibers and mitochondrial tRNA mutation at position 3243 were documented in muscle biopsy. He had diabetes mellitus associated with 3243 mitochondrial DNA mutation, suggesting that clinically, diabetic amyotrophy may be overlapped with mitochondria-related disease entities in some parts. Coenzyme Q10 administration was effective in relieving the symptoms in his legs, fatigue, and residual urine in his bladder. These were confirmed with the improvement in neurological parameters.
In conclusion, this case gives important help in understanding myopathy in diabetes. It would be important to check on the 3243 mitochondrial tRNA mutation in patients with diabetic amyotrophy and/or diabetic neuropathic symptoms.

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The mechanism(s) of an inappropriate secretion of insulin is poorly understood. We report a case of reactive hypoglycemia associated with an unusually exaggerated insulin secretion. The patient, a 32-year-old man, developed frequent episodes of postprandial hypoglycemia after interferon treatment was begun for chronic type C hepatitis. Oral glucose challenge test confirmed the patient's extremely high plasma IRI response, i.e., more than 1000μU/ml, and that of plasma C-peptide 56.9ng/ml at 90 min, followed by symptomatic hypoglycemia (plasma glucose 34mg/dl) at 240min. The plasma proinsulin level also was high, but the molar ratio of immuno reactive insulin (IRI)/plasma C-peptide and IRI/proinsulin was within the normal range. Antibodies to insulin or insulin-receptor were negative. Plasma IRI response was apparently greater when the glucose was given orally than when given intravenously. The response of plasma glucagon-like-peptide (GLP)-1 to oral glucose was quite high (from baseline of 45.5 to 303.2pmol/L) and showed a close parallel with the change in the plasma IRI concentration. The greatly enhanced insulin secretion leading to reactive hypoglycemia in this patient may therefor be attributed to the increased secretion of GLP-1.

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Cabergoline (CG) is a dopamine agonist that inhibits the secretion of prolactin (PRL) and growth hormone. In the present study, we evaluated the in vivo effect of CG on PRL secretion and the pituitary tumor induced by estrogen. Estrogen was administered by subcutaneous injection to 4-weekold Fischer 344 rats weekly for 10 weeks to induce tumors. On the last day of estrogen administration, doses of either CG or bromocriptine (BC), 0.6mg/kg, were administered as a single oral route or chronically, given every third day. Sera and pituitary tumors were sampled on each treatment schedule. Serum levels of PRL were measured and the pituitary glands were weighed. Immunohistological evaluation was performed by optical and electron microscopy. A single dose of CG significantly inhibited the serum levels of PRL for 6 days. Following a single dose of BC, the PRL level was significantly inhibited only at 6 hours' postadministration. The continued oral administration of CG significantly reduced both the serum PRL level and the weight of the pituitary during 15 to 60 days of treatment as compared with BC. Morphologic studies revealed that CG reduced the size of the cells and of the granules, and increased the number of granules per unit area of the cytoplasm. These findings suggest that CG inhibits the maturation of PRL secretory granules and the secretion of PRL more than its synthesis. Thus, CG induced a prolonged lowering of PRL and had a good antitumor effect on rat pituitary tumors induced by estrogen.

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We present a rare case of a 66-year-old woman with the syndrome of inappropriate antidiuresis (SIAD) accompanied by an empty sella whose symptoms were seen twice in the eight years after the administration of non-steroidal anti-inflammatory drugs (NSAID) or prochlorperazine. No diuresis or suppression of the plasma level of vasopressin (AVP) was observed after water loading upon cessation of the causative agents. Suppression of the renin-aldosterone system and a low plasma level of atrial natriuretic peptide (ANP) were observed during natriuresis. The plasma levels of AVP were increased after water loadings. Restriction of water intake ameliorated the symptoms and reduced hyponatremia. These findings suggest that NSAID or prochlorperazine caused overt SIAD twice in eight years. The water loading test itself stimulated the release of AVP and a suppression of the renin-aldosterone system played a more important role in natriuresis than ANP in this case.

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We report two siblings, a 9-year-old boy and 4-year-old girl, with ACTH insensitivity. They were referred to our hospital because of pigmentation of the skin. They had normal plasma cortisol and urinary 17-OHCS levels despite markedly high plasma ACTH, and these did not respond to consecutive 3-day ACTH-Z administration, but plasma aldosterone responded normally to increased plasma renin activity after a low sodium diet. We examined the characteristics of ACTH receptors in peripheral blood mononuclear leukocytes (MNLs) obtained from the patients and their family. Adenylate cyclase generation caused by an addition of ACTH did not occur in MNLs from the patients. In studies on ACTH binding to MNLs, a lack of high-affinity ACTH binding was observed in the patients. These results suggest that the patients have a defect in ACTH binding to the receptors, resulting in ACTH insensitivity. The reason for this defect in ACTH binding remains unclear because no significant mutation in the ACTH receptor DNA sequence was detected in the MNLs of these patients.

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Radioligand assays of the membrane fraction of hen hypothalamic tissues involving the preoptic (HPOA) or median eminence (HMEA) areas revealed the presence of a specific binding component to chicken vasoactive intestinal peptide (cVIP) having properties of a receptor. The equilibrium dissociation constant (K_d) was 0.70±0.07nM (Mean±SEM; N=5) in HPOA and 1.02±0.15nM (N=5) in HMEA as estimated by Scatchard analysis of saturation studies, and was 0.91±0.11nM (N=3) (HPOA) and 1.25 ±0.09nM (N=3) (HMEA) as determined by a kinetic analysis. The maximum binding capacity (B_max) obtained by Scatchard analysis was 167±19fmol/mg protein (N=5) (HPOA) and 133±17fmol/mg protein (N=5) (HMEA). The K_d and B_max values obtained by Scatchard analysis were similar in the two areas of the hypothalamus and in both laying and nonlaying hens. Administration of cVIP in vivo caused a decrease in specific cVIP binding. These results suggest the presence of a VIP receptor in the hen hypothalamus.

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We have shown that cholesterol-fed diabetic rats developed atheromatous lesions in the aorta and coronary arteries, which were not observed in cholesterol-fed diabetic rats receiving concomitant supplementation with 15% glucomannan, a soluble dietary fiber concentrate. The present study was designed to examine the effects of the dietary fiber supplementation on serum levels of glucose and lipoproteins in cholesterol-fed diabetic rats. Feeding a diet containing 1.5% cholesterol (wt/wt) and 0.37% cholic acid for 18 weeks to rats made diabetic by streptozotosin (35mg/kg body weight, iv) produced moderate hyperglycemia and moderate hypercholesterolemia, the latter being characterized by high concentrations not only of low density lipoproteins but also intermediate density lipoproteins and very low density lipoproteins. These changes in serum lipoproteins and hyperglycemia were substantially reduced by 18 weeks of supplementation with glucomannan but high density lipoprotein cholesterol and triglyceride levels did not change after feeding a cholesterol-rich diet in the presence or absence of glucomannan supplementation. These results suggest that amelioration in hyperlipoproteinemia and hyperglycemia induced by the dietary fiber supplementation may help retard or prevent the atheromatous formation found in cholesterol-fed diabetic rats.

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Recent studies demonstrate that apoptosis is an important process in physiological and pathological cell death. We examined the apoptotic phenomena in thyroid tissues by two methods: immunohistological and in situ end-labeling of fragmented DNA (ISEL). In thyroid tissues from patients with Hashimoto's thyroiditis and thyroid cancer, fragmented nuclear DNA and Le^Y (apoptosis associated antigen) were observed. In tissues from patients with Graves' disease, Le^Y and bcl-2 oncoprotein were expressed, but no ISEL positive cells were observed. In contrast, thyrocytes in normal thyroid tissues were not stained with ISEL or anti-Le^Y antibodies (Abs). Fas antigen (Ag) was expressed in various thyroid tissues, including normal subjects. The clinical meaning of this was not determined. These results suggest that the apoptotic process takes place in Hashimoto's thyroiditis and thyroid cancer, and is overcome in Graves' disease by bcl-2 expression.

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Western analyses and immunohistochemistry of transforming growth factor β1(TGFβ1) and TGFβ2 were performed in rat luteal tissue at either the functional or regressing stage. Anti-TGFβ1 or TGFβ2 was localized simultaneously to macrophages within cultured luteal cells and frozen ovarian sections. By Western analysis, an active form of TGFβ (25kDa) was detected clearly with anti-TGFβ2 but only faintly with anti-TGFβ1, and the former band from functional corpora lutea was more intense than that from regressing ones. Treatment with prolactin (PRL), a luteotropic hormone in rodents, also increased the intensity of 25kDa TGFβ2 in the corpus Luteum. Several specific bands with higher molecular weights than 25kDa were also recognized with anti-TGFβ1 or TGFβ2; they are probably ascribed to latent TGFβs and/or TGFβ precursor proteins. In cultured luteal cells and frozen ovarian sections, many anti-TGFβ1 or anti-TGFβ2 positive cells from functional corpora lutea of pseudopregnant rats were double-stained with anti-macrophage. There were numerous macrophages in structurally regressing corpora lutea of pseudopregnant rats, but most of them were not stained with anti-TGFβs. These results suggest that the expression of TGFβ, at least for TGFβ2, is under the influence of PRL in the rat corpora lutea, and that macrophages are responsible for some, if not all, of the Immunoreactive-TGFβ in rat luteal tissue.

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A 46-year-old woman with rheumatoid arthritis had been on non-steroidal antiinflammatory agents for eighteen years until she developed cushingoid features and hypertension resistant to antihypertensive drugs. She had high plasma cortisol and 24h urinary 17-hydroxycorticosteroids (17HCS) which were not suppressed by 8mg dexamethasone per day for two days. The circadian rhythm of plasma cortisol was absent and plasma ACTH concentrations were suppressed before and after intravenous administration of CRH. Abdominal computed tomography demonstrated a tumor (3.0×3.0×2.3 cm) in the right adrenal gland and a ¹³¹I-6 β-19-nor-methylcholesterol scan revealed marked uptake on the same side. The patient underwent a right adrenalectomy and the diagnosis of a cortisol secreting benign adenoma was histologically confirmed. Blood pressure declined and cushingoid features regressed, but three months after the operation and while the patient was on replacement, she complained of pain on motion, marked tenderness and swelling of fingers, wrists, elbows, knees and foot joints, and had very high rheumatoid factors. Treatment with immunosuppressive drugs and oral and intraarticular administration of glucocorticoids were necessary to relieve the clinical symptoms of rheumatoid arthritis. In summary, we report a patient with rheumatoid arthritis and Cushing's syndrome due to an adrenal adenoma, in whom rheumatoid arthritis was exacerbated after curing the Cushing's syndrome. This suggests that it is imperative to follow the development and/or course of autoimmune diseases after the treatment of Cushing's syndrome.

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To seek the pathophysiologic significance of measuring the concentration of total renin instead of prorenin, we determined the plasma total renin concentration by immunoradiometric assay and correlated the results with various clinical features and laboratory parameters of diabetic complication in 108 patients with diabetes mellitus. The plasma prorenin concentration was estimated as the difference between the total and active renin concentrations. The plasma total renin and prorenin concentrations were high in patients with diabetes mellitus, in contrast to the active renin concentration which was slightly decreased. In addition, the plasma total renin and prorenin concentrations were higher in patients with diabetic complications than in patients without any complication. Multiple regression analysis showed that the presence of orthostatic hypotension, diabetic retinopathy, and proteinuria is significantly associated with the increased plasma total renin and prorenin concentrations. In addition, there was a significant positive correlation between the total renin and prorenin concentrations. These results suggest that both the plasma total renin concentration and the prorenin concentration are closely related to diabetic complications. Determination of the plasma total renin concentration by immunoradiometric assay as a substitute for prorenin could be a powerful tool in elucidating the mechanism for the increased plasma prorenin in diabetes mellitus.

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We studied PRL release from individual pituitary cells in normal and estrogen (E₂)-treated female Fischer 344 rats by means of a reverse hemolytic plaque assay. In this assay, the area of the hemolytic plaque around a pituitary cell is proportional to the amount of hormone secreted from the cell. Multimodal distribution of the plaque area was observed in normal pituitary cells, and was unchanged in the course of aging. In E₂-treated pituitary cells, bimodal distribution was found. The heterogeneity of the distribution pattern (functional heterogeneity) and PRL secretion from a single pituitary cell decreased in association with the length of E₂ treatment. The mean plaque area for the E₂-treated pituitary cells was smaller than that for the normal pituitary cells. These results suggest that in E₂-treated pituitary cells, the functional heterogeneity and PRL release from a single cell decrease as tumorigenesis progresses.

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The RET proto-oncogene is expressed in human medullary thyroid carcinoma and pheochromocytoma.Recently germline mutations of the RET proto-oncogene were reported in four syndromes (MEN 2A, MEN 2B, familial medullary thyroid carcinoma and Hirschprung's disease) and somatic mutation was also found in sporadic medullary thyroid carcinoma. To determine the incidence of RET mutations in medullary thyroid carcinoma in Japan, we investigated 14 medullary thyroid carcinomas (comprising 1 case of MEN 2A, 1 case of MEN 2B, 2 cases of familial medullary thyroid carcinoma and 10 cases of sporadic). Tumors from all cases were screened by PCR-SSCP on exons 10 and 11. DNA sequencing on these exons was performed for the hereditary medullary thyroid carcinoma cases. The PCR products of exon 16 from tumor DNA were analyzed by means of Fok1 restriction enzyme digestion analysis and mutations confirmed by DNA sequencing. We found no structural abnormalities in either exon 10 or exon 11 in any of the cases examined, but in four of 10 sporadic cases we detected a common point mutation at codon 918 (ATG to ACG) in exon 16, where methionine was replaced with threonine. Our results support the theory that a point mutation of exon 16 of the RET proto-oncogene may be related to the oncogenesis of sporadic medullary thyroid carcinomas. However, further studies on the entire RET proto-oncogene are needed to clarify the relationship between its expression and thyroid tumorigenesis.

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The effect of luteinizing hormone releasing hormone (LHRH) on the neuronal activity of CA1 and CA3 regions of the hippocampus was studied by means of extracellular recordings in the castrated male, intact male, castrated female, and castrated female injected s.c. with 20μg estradiol benzoate (EB) for 3 days. The basal firing rate of the CA3 neurons of castrated EB-treated female rats was significantly lower than that of the neurons in castrated EB-untreated female rats as well as male rats, either intact or castrated, whereas that of the CA1 neurons was not significantly different from castrated EB-untreated female rats. Iontophoretically applied LHRH predominantly resulted in facilitation of the neuronal firing in most of the animal groups. In the CA3 region of castrated EB-treated female rats, however, inhibition occurred in a large percentage of neurons, and the ratio of facilitation, inhibition and no response was significantly different from that in castrated EB-untreated female rats. In the CA1 region of castrated EB-treated female rats, the predominant effect of LHRH was facilitation and the ratio of facilitation, inhibition and no response was not significantly different from that in castrated EB-untreated female rats. These results suggest that LHRH is involved in increasing the neuronal activity of the CA3 region in the hippocampus, and estrogen reduces this LHRH action.

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Macrophages from recent onset non-obese diabetic (NOD) mice showed cytotoxicity against the NOD mouse derived beta-cell line, MIN6N-9a. In this report, we examined whether nitric oxide is associated with beta-cell destruction. Peritoneal exudate cells (PEC), obtained from cyclophosphamide treated NOD mice showed higher cytotoxicity against MIN6N-9a compared to PECs from saline injected NOD mice (P<0.01). This effect was suppressed in cells incubated with 0.5mmol/lN^G-methyl-L-arginine, a nitric oxide synthase inhibitor (P<0.001). In addition, the nitrite concentration of the co-culture medium, as an index of nitric oxide production, increased in MIN6N-9a cells co-cultured with peritoneal exudate cells from cyclophosphamide injected NOD mice but not in co-culture with saline injected NOD mice (P<0.05). Thus, nitric oxide plays an important role in beta-cell line destruction of macrophages obtained from NOD mice.

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Sporadic pheochromocytomas, sporadic medullary thyroid carcinomas (MTCs), pheochromocytomas and/or MTCs in multiple endocrine neoplasia (MEN) 2A or 2B were screened for mutations in the tyrosine kinase domain of the RET proto-oncogene by direct sequencing of PCR-amplified products or sequencing subcloned DNAs from PCR-products. All tumors of 4 MEN 2B patients were confirmed to contain a heterozygous missense mutation at codon 918 (ATG→ACG; Met→Thr) of the RET proto-oncogene as well as their leukocytes. The same tumor-specific mutations at codon 918 were also found in 5/16 (31%) sporadic pheochromocytomas. These results suggest that mutations of the RET proto-oncogene in its tyrosine kinase domain play a role not only as the predisposing gene for MEN 2B, but also as a tumorigenic factor for pheochromocytomas of sporadic type.

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In order to elucidate whether exercise and calcium intake can offset bone loss due to hypoestrogenemia in teenage girls, the lumbar and femoral bone mineral density (BMD) in elite amenorrheic runners (group 1 (n=8)) was compared with those in eumenorrheic athletes (group 2 (n=15)) and two groups of eumenorrheic non-athletic subjects, group 3 (n=14), and group 4 (n=15). BMD was measured by dual energy x-ray absorptiometry. The subjects in group 1 lived in the dormitory, and their calcium intake was controlled to >1400mg/day. The subjects in groups 1, 2 and 3 were age matched (16-17 years old), but the body weight of those in group 2 was significantly greater than that of others. The subjects in groups 1, 3 and 4 were weight matched, but group 4 subjects were older by 5 years (21.0 ±0.2 years old). The lumbar BMD of group 1 was 1.0460±0.0259, which was not statistically different from those in the other groups, while the femoral BMD of group 1 was significantly higher than those of groups 3 and 4 at trochanter. The lumbar and femoral BMD of group 2 was significantly higher than in groups 3 and 4, but was not statistically different from group 1. There were no significant differences in serum parathyroid hormone levels, but osteocalcin and calcitonin levels of group 1 were significantly lower than those of groups 2 and 3, and groups 2, 3 and 4, respectively, suggesting that the rate of bone formation is suppressed in amenorrheic runners. These results indicate that the physical activity during the teens can offset bone loss due to exercise-induced amenorrhea, but the effect seems to be temporary because the rate of bone formation has been altered in these girls.

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To investigate the histopathological features of atrophic thyroiditis (AT) with blocking type-TSH binding inhibitor Immunoglobulins (TBII), the present morphological observations were carried out employing additional immunohistochemical procedures. Moreover, these were compared with examples of goitrous Hashimoto's thyroiditis showing negative TBII (HT). There exist apparent differences between AT and HT. In particular, significant follicular atrophy with epithelial flattening including decreased positive staining of the follicular epithelial cells for thyroglobulin in AT was characteristically observed. These results suggest that the mechanism for the development of hypothyroidism in AT with blocking type-TBII might be due to suppression of thyroid cell function through the inhibition of endogenous TSH stimulation by the blocking antibody with subsequent epithelial degenerative destruction.

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A 28-year old female patient with virilization due to left adrenocortical adenoma was studied. The patient had clinical features of hyperandrogenism such as hirsutism and a low pitched voice, but not of hypercorticoidism. Plasma testosterone and dehydroepiandrosterone-sulfate (DHEA-S) were high. Although the basal plasma cortisol concentration and urinary excretion of 17-hydroxycorticosteroids (17-OHCS) were within the normal range, the absence of diurnal variation in plasma cortisol and loss of suppressibility by dexamethasone suggested constitutive secretion of cortisol by the tumor. Inappropriate cortisol secretion was also supported by blunted ACTH response to provocative stimuli. After successful removal of the left adrenal tumor, such endocrinological abnormalities were all normalized. Immunohistochemical analysis revealed that tumor cells were positively stained for C21 hydroxylase cytochrome P-450 (P-450_C21) and P-450_11β which convert 17-hydroxy (OH) progesterone to cortisol as well as P-⁴⁵⁰SCC, 3β-hydroxysteroid dehydrogenase and P-450_17α which are involved in testosterone biosynthesis. These findings suggest that adrenocortical adenoma secretes predominantly testosterone and constitutively cortisol in a young woman patient with virilization.

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Presence of alternatively spliced-estrogen receptor (ER) mRNA variants has been revealed in the breast cancer tissues. The ER variants transcribed from these mRNA variants were supposed to cause changes in the estrogen responsiveness of breast cancer. Although uterine endometrial cancer also has an estrogen-dependent profile, these ER mRNA variants have not yet been reported in the tumor. In the present study, we attempted to detect the exon 7 deletion- (del.7-) and exon 5 deletion (del.5) ER mRNA variants in normal human uterine endometrium (hEM) and uterine endometrial cancer tissue (hEC) by the use of reverse transcription-polymerase chain reaction-Southern blotting (RT-PCR-SB) with the PCR primers: hE4 (forward), hE6 (reverse), and hE8 (reverse), which were located in exons 4, 6, and 8, respectively. Two major products were generated from RNAs of both hEM and hEC with primers hE4 and hE8. The nucleotide sequence of the longer product was identical to exon 4-8 of human ER cDNA, whereas that of the shorter one completely deleted exon 7. Moreover, when the RT-PCR was done with the primers hE4 and hE6, the shorter product lacking exon 5 was detected with the longer one having the same sequence as exon 4-6 of human ER cDNA. Since the RT-PCR-SB with primers hE4 and hE8 produced a very low or undetectable level of the signals corresponding to del.5 ER mRNA variant, the level of del.7 ER mRNA variant seemed to be higher than that of del.5 ER mRNA variant. These results strongly suggested that both del.7- and del.5 ER mRNA variants exist in the normal uterine endometrium as well as in endometrial cancer. The ER variants, possibly expressed in these tissues, may play a physiological and/or pathological role.

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We encountered a 33-year-old female patient with a pituitary growth hormone (GH)-secreting macroadenoma. The patient was treated with somatostatin analogue (Octreotide) in combination with bromocriptine for 2 months before a transsphenoidal adenomectomy was carried out. Octreotide (300-800μg/day) in combination with bromocriptine was effective in reducing the size of the adenoma by 36%, but produced only a marginal decrease in serum GH. After the operation, bromocriptine alone (15 mg/day) did not lower the level of GH which was produced by residual adenoma tissue. When octreotide (200μg/day) was resumed along with the bromocriptine one year after the operation, it effectively lowered serum GH for 6 months. Thereafter, octreotide therapy became ineffective with a concomitant rise in serum GH and somatomedin C, which was not accompanied by an increase in tumor size. This was a rare case of acromegaly that showed desensitization to octreotide after long-term treatment.

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Although increased plasma fibronectin (PF) levels have been found in diabetic patients with microalbuminuria, there is still controversy about its clinical implication for detecting early diabetic nephropathy. To evaluate the PF concentration as a possible marker for early diabetic nephropathy, three groups of sex-and age-matched patients were studied I) 22 insulin dependent diabetic (IDDM) patients with microalbuminuria (mean age±SEM: 23.3±3.6 years, mean urinary albumin excretion rate (AER)±SEM: 47.1±39.5μg/min); II) 17 IDDM patients with normoalbuminuria (mean age: 23.4±4.4 years, mean AER: 7.8±2.1μg/min) and III) 20 healthy control subjects (mean age: 22.6±4.1 years, mean AER: 6.7±2.1μg/min). PF and urinary excretion of albumin were measured by an immunoturbidimetric method using commercially available kits (Boehringer Mannheim GMBH FRG, and Miles Lab., UK). The mean PF was significantly higher in the group with microalbuminuria (406.5±122.9μg/ml) than in the group with normoalbuminuria (295.6±96.9μg/ml, P<0.01) or in the control group (299.54±105.5 μg/ml, P<0.01). A weak positive correlation was found between PF and urinary albumin values (r=0.35, P<0.05). There were no significant correlations between PF and the other variables such as age, duration of diabetes, body mass index, arterial blood pressure, fasting blood glucose, fructosamine and HbA1 in the diabetic patients or in the control group. Our results suggest that the PF concentration could be a weak marker for early diabetic nephropathy. We cannot therefore use PF instead of microalbuminuria because there is only a weak correlation between PF and microalbuminuria.

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