Membrane-bound cell surface peptidases including aminopeptidase-N (EC 3.4.11.2), dipeptidyl peptidases IV (EC.3.4.14.5), carboxypeptidase-M (EC 3.4.17.12), neutral endopeptidase (EC 3.4.24.11) and endothelia converting enzyme-1 (EC 3.4.23) were shown to be differently expressed on human ovarian granulosa, theca interna and luteal cells and on endometrial epithelial and stromal cells. These peptidases have their catalytic sites extracellularly and can metabolize biologically active peptides at the cell surface, serving as local regulators of peptide concentrations. In the ovary and endometrium, numerous peptides are considered to be locally produced and play an important role in the follicular growth, ovulation, corpus luteum function, endometrial differentiation and embryo implantation in an autocrine and/or paracrine fashion. The inhibition of aminopeptidase activity by bestatin affected murine follicular growth, steroidogenesis by porcine ovarian cells and progesterone-induced decidualization of human endometrial stromal cells in vivo or in vitro. These findings suggest that membrane-bound peptidases are important regulators of the function and differentiation of the ovarian cells and endometrial cells including embryo. In the near future, the physiological roles of these peptidases will be clarified and clinical use of peptidase inhibitors may be applied to the various reproductive disorders.

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CLA-1, a human homologue of rodent scavenger receptor class B1 (SR-B1), has been identified as a receptor for high density lipoprotein (HDL) and is highly expressed in the adrenal gland. Several studies have indicated that HDL might be a source of cholesterol for steroidogenesis in the adrenal gland. In this study, we show that ACTH and its second messenger cAMP stimulated CLA-1 protein expression in a human adrenocortical cell line. We also determined whether CLA-1 plays an important role in steroidogenesis by investigating CLA-1 expression levels in various adrenal tumors including the adenomas of Cushing's and Conn's syndrome. Western blot analysis showed that CLA-1 expression was much higher in the tumors of Cushing's syndrome than in non-tumor lesions of Conn's syndrome and pheochromocytoma. We were able to detect a strong CLA-1 signal in tumors of Conn's syndrome, too. On the other hand, much less CLA-1 expression was detected in Cushing's adenoma adjacent adrenal glands. The immunohistochemical analysis showed that CLA-1 was expressed in the outer region of the adrenal cortex mainly in plasma membranes of the cortical cells but not in the medulla. These findings demonstrated for the first time that ACTH increased CLA-1 protein in cultured human adrenocortical cells, and that cortisol- and aldosterone-secreting adenomas had high CLA-1 proteins in their cell surfaces.

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A 64-year-old woman was admitted in November, 1996 for fluctuating blood pressure. There was multinodular goiter in her neck. High urine VMA and serum aldosterone were noted. Computed tomography showed an oval lesion in the left adrenal gland. Left adrenalectomy was performed and the pathology was proved to be adrenal cortical nodular hyperplasia. Fluctuating blood pressure and high urine VMA persisted after the operation. CT scan of the abdomen revealed a soft tissue mass in lower abdomen. The patient was admitted again in September, 1997. Laboratory examinations showed normal serum aldosterone, normal plasma renin activity and high urine VMA. Aspiration cytology of the thyroid gland disclosed papillary thyroid carcinoma. [¹³¹I]-metaiodobenzylguanidine image revealed a high uptake lesion in the right L-3 paravertebral area. Tumor excision and thyroidectomy were performed. The pathology was reported as extraadrenal pheochromocytoma and papillary thyroid carcinoma. Papillary thyroid carcinoma is rarely associated with pheochromocytoma. To our knowledge, this paper is the first report of a patient with extraadrenal pheochromocytoma associated with papillary thyroid carcinoma and adrenal cortical nodular hyperplasia.

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Pancreatic and duodenal homeobox gene-1(PDX-1) is a transcription factor which regulates the insulin gene expression. In this study, we tried to elucidate the role of PDX-1 in the glucose-induced transcriptional activation of the human insulin gene promoter in MINE cells. Electrophoretic mobility shift assay (EMSA) and chloramphenicol acetyltransferase (CAT) assay demonstrated that both DNA-binding activity and transcriptional activity of PDX-1 were increased with 20mmol/l glucose more than with 2mmol/l glucose. The DNA-binding activity of PDX-1 induced by high glucose was blocked by phosphatase treatment, suggesting the involvement of PDX-1 phosphorylation in this event. In an in vitro phosphorylation study, PDX-1 was phosphorylated by protein kinase C (PKC), but not by cAMP dependent protein kinase (PKA) or mitogen-activated protein kinase (MAPK). Furthermore, increased PDX-1 function induced by high glucose was blocked by calphostin C, an inhibitor of all PKC isoforms, but unaffected by phorbol 12-myristate 13-acetate (PMA), an activator of classical and novel PKC, or Gö 6976, an inhibitor of classical and novel PKC, which suggested that the PKC family which activated PDX-1 in MINE cells was atypical PKC. Western blot and immunocytochemical studies with anti-PKCζ antibody confirmed the presence of PKC ζ, one of the isoforms of atypical PKC, in MIN6 cells. Furthermore, PKC ζ activity was significantly increased by glucose stimulation. These results suggest that high glucose increased DNA-binding activity of PDX-1 by activating atypical PKC including PKC ζ, resulting in transcriptional activation of the human insulin gene promoter.

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We report a case of preclinical Cushing's syndrome in a 54-year-old male associated with bilateral adrenocortical tumours. Physical findings and general laboratory data were unremarkable except for mild hypertension (158/90mmHg) and impaired glucose tolerance. Endocrinological evaluation revealed the presence of autonomous cortisol secretion including unsuppressible serum cortisol by 8 mg dexamethasone test (11μg/dl), high serum DHEA-S (3580ng/ml, normal: 400-3500) and increased urinary 17-KS excretion (31.0-35.8mg/day, normal: 5.8-21.3). CT scan demonstrated the presence of tumours in both adrenals and bilateral adrenalectomy was subsequently performed. Histological examination of the resected specimens revealed an adrenocortical carcinoma on the right side and an adenoma on the left side with noticeable cortical atrophy in non-neoplastic adrenals. Immunohistochemical study of steroidogenic enzymes demonstrated that all the steroidogenic enzymes involved in cortisol biosynthesis were expressed in both right and left adrenal tumours. Enzymatic activities of 21, 17α, 18, 11β-hydroxylases were detected in both right and left adrenals except for the absence of 11β-hydroxylase activity in the left adrenal adenoma. Results of in vitro tissue steroidogenesis examined in short-term tissue culture of the specimens revealed no significant differences between carcinoma and adenoma in cortisol production, but the production of adrenal androgens in carcinoma was significantly higher than that in adenoma, which may indicate the importance of evaluating adrenal androgen levels in patients with adrenocortical neoplasms.

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Asialoglycoprotein (ASGP) receptor, which exists in hepatic parenchymal cells, plays important roles in the clearance of desialylated glycoproteins from the circulation. To study the expression of ASGP receptor in human fetal liver, specimens were obtained after therapeutic/spontaneous abortion or at autopsy with informed consent. Reverse transcription polymerase chain reaction and immunohistochemical staining showed that ASGP receptor was present as early as 15 weeks of gestation in human fetal liver. In liver at 15 weeks-gestation it was stained uniformly in cytoplasm as seen in HepG2 cells. As gestation proceed the ASGP receptor was frequently observed on the cell surface and intracellular staining showed a spotted distribution. We conclude that the expression of ASGP receptor is an early event in the developmental process of fetal liver. Furthermore, the distribution of ASGP receptor changes as the liver develops.

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It has been reported that there is an inverse relationship between serum sodium (Na) and potassium (K) levels in patients with diabetic coma. The present study was undertaken to determine whether such an inverse relation depends upon plasma glucose levels in diabetic patients for their glycemic control. We examined two hundred and fifty-two patients with diabetes mellitus admitted to our hospital during the one-year period to control their plasma glucose levels, except for those having nephropathy or liver dysfunction. Serum Na and K, plasma glucose, and serum and urinary C-peptide levels were determined. There was a negative correlation between serum Na levels and fasting plasma glucose (FPG), and, conversely, a positive correlation between serum K levels and FPG. The changes were more evident in the patients with insulin-dependent diabetes mellitus than those with non-insulindependent diabetes mellitus. There was an inverse relation between serum Na and K levels and it was profoundly dependent upon plasma glucose levels in all the diabetic patients before tight control of their glycemic levels. The disorder may be based on the movement of electrolytes between intra- and extracellular spaces, dependent on the impaired insulin action as well as hyperosmolality.

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Uterine leiomyomas develop from uterine smooth muscle cells, which are known to be regulated by estrogen and other growth factors. The purpose of this study was to investigate the role of expression of parathyroid hormone related-peptide (PTHrP) in the growth of uterine leiomyomas treated or untreated with gonadotropin-releasing hormone agonist (GnRH-a). Thirty-nine leiomyoma tissues were obtained from 36 patients who had been treated with GnRH-a (n=10) or without GnRH-a (n=29). The intensity of PTHrP immunostaining was categorized into three grades; “negative”, “weakly positive”, and “positive”. Leiomyoma cell growth was estimated by the proliferating cell nuclear antigen (PCNA) labeling index (LI) with an image analyser. We also investigated the correlation between PTHrP expression and cell proliferation or histopathological findings. In the GnRH-a-untreated group, LI of the PTHrP “positive” group was significantly higher than that of the PTHrP “negative” group, but the intensity of PTHrP immunostaining did not correlate with LI in the GnRH-a-treated group. PTHrP expression did not correlate with histological findings or clinical parameters (age and phase of menstrual cycle) in either the GnRH-a-treated or the -untreated group. In addition, the expression of mRNA for PTHrP and its receptor was detected in leiomyomas by reverse transcriptase-polymerase chain reaction (RT-PCR). Our results indicate that the expression of PTHrP in leiomyomas correlated positively with cell growth in the GnRH-a-untreated group, suggesting that PTHrP may act as a local cell growth modifier in an autocrine/paracrine fashion on uterine leiomyomas.

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To evaluate the significance of the extrathyroid extension (ETE) of papillary thyroid carcinoma at the time of diagnosis and the prognostic variables of patients, we retrospectively reviewed 1, 013 thyroid cancer patients. Of the 741 papillary thyroid cancer patients, 466 (62.9%) were categorized in clinical stage I and 114 (15.4%) were categorized in clinical stage III. Of the 114 patients in clinical stage III, 81 were female (mean age 44.4±15.7 years) and 33 were male (mean age 46.9±18.1 years). Of the clinical stage III patients, 104 patients received post-operative radioactive iodide (¹³¹I) therapy while 22patients received external radiotherapy in the neck and upper mediastinum area post-operatively. In the study, age, gender, ¹³¹I accumulated dose, post-operative serum thyroglobulin (Tg) levels, and survival rate were demonstrated to be statistically significant in the groups with no recurrence and recurrence after treatment. The average follow-up period of these patients was 6.0 years. During this follow-up period, 11 patients expired. Eight died of thyroid cancer (7.0%) and 3 died of intercurrent diseases including asthma, renal cell carcinoma and propranolol overdose. Four of the 8 patients (50%) died of airway obstruction due to cancer cell invasion. Another 4 died of distant metastases, including 2 patients with skull metastases and brain invasion. The 5- and 10-year survival rates were 0.981 and 0.956 in clinical stage I and 0.923 and 0.843 in clinical stage III, respectively. In conclusion, the survival rate of the ETE of papillary thyroid cancer was lower when compared with stage I, especially in older male patients with higher post-operative serum Tg levels.

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Systemic and nonspecific stress response effects on the cellular defense mechanism were studied in the male rat kidney. Two days after laparotomy-induced surgical stress, rats showed increased serum corticosterone and renal cortical reduced glutathione (GSH). Rats were then injected s.c. with mercuric chloride (HgCl₂) to oxidatively injure renal tubuli. Increased serum creatinine levels indicated that laparotomy pretreatment lessened renal damage. To study the effects of the activated pituitary-adrenal axis on renal cortical GSH content and vulnerability to subsequent oxidative injury, rats were injected s.c. with ACTH on two consecutive days. ACTH administration increased both corticosterone and aldosterone. These rats showed increased, dose-dependent renal cortical GSH content, i.e., controls (n=7): 1.25±0.23μmol/g tissue, daily dose of 10μg/100gBW (n=7):1.53±0.24 μmol/g tissue, and daily dose of 40μg/100gBW (n=7): 2.31±0.23μmol/g tissue. Rats receiving daily doses of 40μg of ACTH/100gBW acquired resistance to oxidative injury, indicated by serum creatinine levels: controls (n=6), 22±4μmol/L; HgCl₂ (n=6), 145±88 μmol/L; ACTH and HgCl₂ (n=6), 37±11 μmol/L. Morphological evidence indicated that ACTH pretreatment in HgCl₂-injected rats prevented renal tissue from inflammatory cell infiltration but not from tubular degeneration. Cellular GSH content of LLC-PK1 cells, porcine renal-tubule-derived culture cells, increased significantly in incubation with dexamethasone or aldosterone, suggesting that adrenal steroids directly stimulate renal cell GSH. We demonstrated that stress or ACTH administration activates the defense mechanism in the kidney via increased GSH. This stress-activatable defense system may therefore indicate a connection between endocrine stress response and the cellular defense mechanism.

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Intracellular generation of triiodothyronine (T₃) from thyroxine (T₄) by type 2 deiodinase (D2) in the mammalian brain, plays a key role in thyroid hormone action. The presence of D2 in rat astrocytes suggests the importance of glial cells in the regulation of intracellular T₃ levels in the rat central nervous system (CNS). To analyze further the factors that regulate D2 activity in the CNS, we investigated the effects of nicotine and of mecamylamine, which inhibits the binding of nicotine with nicotinic acetylcholine receptors, on D2 activity in cultured mixed glial cells of the rat brain. We incubated cultured mixed glial cells obtained from neonatal Wistar rats in the presence of 10mM dithiothreitol, 2nM [¹²⁵I] reverse T₃ and 1mM 6-N-propyl-2-thiouracil for 2 h at 37°C, and the released ¹²⁵I- was counted in a γcounter. D2 activity of cultured cells was dependent on the temperature and the amount of protein. The basal D2 activity of rat mixed glial cells was 1.9±0.2fmol of I^- released/mg protein/h (mean±SEM). The addition of 10^-11, 2×10^-11, 10^-10, and 10^-9M nicotine significantly increased D2 activity to approximately 2.2-, 2.4, 3.5- and 2.9-fold the basal level, respectively. D2 activity stimulated by 10^-8M nicotine (2.5-fold) reached a peak after 9h incubation. The stimulatory effect of nicotine was completely blocked by 10^-6M mecamylamine. In conclusion, nicotine increases D2 activity probably via nicotinic acetylcholine receptors, and may influence brain function, at least in part, by affecting thyroid hormone metabolism.

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Five hyperthyroid patients with TSH-secreting pituitary adenoma were treated with octreotide. Acute administration of octreotide decreased plasma TSH levels in all patients (mean decrease, 50.6±14%). Treatment with octreotide (25-300μg/day) for 2-360 weeks resulted in reductions in plasma TSH and α-subunit levels in three patients, and serum free thyroxine levels were normalized with concomitant clinical improvements such as disappearance of excessive sweating, tachycardia and finger tremors. In two patients, plasma TSH and free thyroxine levels were initially decreased, but tachyphylaxis occurred 3 and 10 weeks after the initiation of therapy. Mild to marked shrinkage of the tumor was observed 2-50 weeks later in four patients. Shrinkage of the tumor seems to be reversible in one case. Frequent bowel movements and epigastric discomfort occurred in two patient. Somatostatin receptor subtype 2 (sst₂) mRNAs were detected in two adenoma tissues studied by RT-PCR. Long-term treatment with octreotide is effective in controlling hyperthyroidism and tumor growth in patients with TSH-secreting pituitary adenoma.

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Human growth hormone with 22, 000 Dal (22K-hGH) stimulates proliferation and differentiation of osteoblasts as well as production of interleukin-6 in vitro and bone formation and remodeling in vivo. To investigate whether hGH isoform with 20Kd (20K-hGH), which accounts for 10% of circulating hGH, elicits similar metabolic effects on skeletal tissues, we studied the biological effects of 20K-hGH in cultured human osteoblast-like cells (HOB). HOB were obtained from trabecular bone explants and cultured in α-MEM supplemented with 10%FCS. In subconfluent cultures, 22K- and 20K-hGH stimulated [³H]thymidine incorporation by 62±27% and 63±23%, respectively (mean±SD, n=8, P>0.1). In confluent cultures, 22K- and 20K-hGH increased alkaline phosphatase activity by 38±23% and 41±23% (P>0.1), respectively, and increased the osteocalcin concentration in the presence of 10^-9M 1, 25-(OH)₂D₃ by 50% and 47% (P>0.1), respectively. Furthermore, both hGHs doubled the interleukin-6 (IL-6) concentration in the conditioned medium. RT-PCR analysis revealed that 22K- and 20K- hGH increased IL-6 gene expression 2.2±0.6 and 2.4±0.7 -fold, respectively. In summary, we have demonstrated that 20K-hGH elicits equipotent anabolic effects on HOB and stimulates to the same extent the production of IL-6, a cytokine which initiates osteoclastogenesis. These in vitro findings suggest that 22K- and 20K-hGH may equipotently stimulate bone remodeling and elicit anabolic effects on skeletal tissue when administered in vivo.

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We encountered a 58-year-old woman with acromegaly accompanied by a cortisol-secreting adrenal tumor without clinical features of hypercortisolism. The simultaneous occurrence of these two endocrinopathies in one individual is extremely rare. She was diagnosed as having diabetes mellitus 8 years ago. Afterwards, in spite of insulin therapy, her hyperglycemia could not be well controlled. Her acromegaly and preclinical Cushing's syndrome were histopathologically proven to be due to a pituitary adenoma and an adrenocortical adenoma, respectively. Successful treatment for these endocrinopathies resulted in greatly improved blood sugar control because of a reduction in insulin resistance. In this case of preclinical Cushing's syndrome, replacement therapy with glucocorticoid was able to be discontinued at only 8 weeks after adrenalectomy, so that the period of necessary replacement was much shorter than that for overt Cushing's syndrome. This is the first report describing insulin resistance before and after treatment in a case of acromegaly accompanied by adrenal preclinical Cushing's syndrome.

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Neuropeptide Y (NPY) is a potent vasoconstrictor peptide that is abundant in the brain and the peripheral sympathetic nervous system. In the present study we investigated possible changes in plasma immunoreactive (IR)-NPY concentrations and urinary IR-NPY excretion in patients with non-insulin dependent diabetes mellitus (NIDDM) and the relationship to diabetic complications, such as nephropathy and neuropathy. IR-NPY in plasma and urine was measured by radioimmunoassay in 69 patients with NIDDM. Plasma IR-NPY concentrations in patients with advanced nephropathy (creatinine clearance <30ml/min) (100.5±10.3pmol/l, n=9, mean±SEM) were higher than in the control subjects (55.0±6.8 pmol/l, n=15) (P<0.02). Urinary excretion of IR-NPY and fractional excretion of NPY were also increased in the patients with advanced nephropathy. Sephadex G-50 column chromatography of the urine extracts obtained from healthy subjects, diabetic patients with renal failure and non-diabetic patients with renal failure showed an immunoreactive peak eluting in the NPY position. On the other hand, neither plasma nor urinary IR-NPY was high in patients with retinopathy, or in patients with peripheral neuropathy. The present study has, for the first time, shown high plasma IR-NPY concentrations and urinary IR-NPY excretion in NIDDM patients with advanced nephropathy.

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We report a rare case of acromegaly in which pituitary infarction possibly developed in a GH-producing pituitary adenoma following gastrointestinal bleeding from peptic ulcer. In this case, pituitary infarction resulted in spontaneous remission of acromegaly associated with diabetes mellitus. In addition, detailed histological investigation revealed that clinically silent pituitary apoplexy was mainly an acute ischemic event which occurred recently in a GH-producing adenoma. This event led to massive coagulation necrosis of the tumor and endocrinological improvement.

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In hope of understanding possible roles of estrogen during early embryogenesis, we examined the expression of both estrogen receptor α (ERα) and ERβ, a recently cloned novel subtype, in mouse oocytes and preimplantation embryos by means of reverse transcription polymerase chain reaction (RT-PCR). To investigate whether estrogen actually exerts its action, we further determined the expression of efp (estrogen-responsive finger protein), a newly characterized estrogen responsive gene belonging to the RING finger family. ERα mRNA was detected in whole ovaries, cumulus-oocyte complexes, denuded oocytes, 2-cell and 4-cell embryos, whereas it was undetected in 8-cell embryos. Interestingly it reappeared in morulae and blastocysts. ERβ mRNA was detected similarly to ERα except for the absence of ERβ mRNA in morulae. The efp mRNA was detected in whole ovaries, cumulus-oocyte complexes, 4-cell embryos, morulae and blastocysts. The stage specific expression of ERα and ERβ along with detection of the product of the estrogen responsive gene in early preimplantation embryos may indicate the possible physiological roles of estrogen in early embryogenesis.

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A 48-year-old female presented with acromegaly, amenorrhea and hyperthyroidism associated with high serum free T4 levels and measurable TSH concentrations. The administration of GHRH induced significant increases in GH, PRL and TSH. Conversely, intravenous infusion of dopamine or oral administration of bromocriptine effectively inhibited GH, PRL and TSH secretion. Serum α-subunit levels were neither affected by GHRH, dopamine nor bromocriptine. Transsphenoidal surgery was performed and immunostaining of the tissue showed that the adenoma cells were positive for GH, PRL or TSH. The patient was treated with bromocriptine at a daily oral dose of 10mg after surgery. Serum TSH were initially suppressed but returned within reference intervals with persistent normalized free T₄ levels. Serum PRL became undetectable and GH levels were stable around 6ng/ml except the periods of poor drug compliance, when serum TSH, GH and PRL levels rose considerably. The patient was followed-up for 10 years without any change in the residual adenoma tissues as detected by magnetic resonance imaging. These findings suggest that long-term bromocriptine therapy is effective in treating the hypersecretory state of a plurihormonal adenoma secreting TSH, GH and PRL.

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We report a case of a 23-year-old Japanese woman who had severe hyperparathyroidism associated with chronic renal failure before the start of dialysis treatment. Her chief complaints were swelling and pain in both shoulders. Laboratory examination revealed renal failure (BUN 134mg/dl, serum Cr 7.3mg/dl), severe normocytic normochromic anemia (hemoglobin 4.3g/dl), hypercalcemia (11.8mg/dl), and hyperphosphatemia (9.7mg/dl). Serum PTH levels were extremely increased (intact PTH>1, 000pg/ml: normal range 10-50pg/ml). X-ray examination of the skull and shoulders showed a salt and pepper appearance, and cauliflower-like deformity of the distal end of both clavicles, respectively. Accelerated ectopic calcification was observed in the costal cartilages, internal carotid arteries, and splenic arteries. Ultrasonographic examination revealed enlargement of the four parathyroid glands. Thallium-technetium subtraction scintigraphy of the parathyroid glands showed increased uptake into the upper two. Renal needle biopsy revealed severe impairment of the interstitium and tubules with much milder changes in glomeruli. The etiology of the renal failure could not be identified. Hemodialysis, total parathyroidectomy and auto-transplantation into the forearm were immediately performed. The pathological diagnosis was chief cell hyperplasia of the parathyroid glands. Based on the presence of chronic renal failure, remarkable hyperphosphatemia with mild hypercalcemia, an unusually high level of serum PTH, and accelerated ectopic calcification, the patient was diagnosed to have severe secondary hyperparathyroidism caused by chronic renal failure with major impairment of the renal interstitium and tubules.

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The patient was a woman of forty-eight. Liver dysfunction was pointed out at the age of forty-five. She was admitted to hospital because of her hyperthyroidism. Her palmar skin was wet and her fingers were swollen like sausages. She had a diffuse and elastic hard goiter with a rough surface. The serum levels of free T₃ (9.6pg/mL) and free T₄ (3.76ng/dL) were high and that of TSH (0.11μU/mL) was low. The activity of TSH-binding inhibitory immunoglobulin (TBII) was 89%. The uptake rate of ¹²³I to the thyroid was 55.1% and the uptake pattern was nearly diffuse. The goiter was proved to contain several nodules by ultrasonography, but aspiration cytology showed no malignant cells. She was diagnosed to have Graves' disease with adenomatous goiter. She also had high ALT (34IU/L) and γ-globulin (1.97g/dL). She had positive antinuclear antibody (speckled type), positive anti-ribosomal nuclear protein antibody, and positive LE cell phenomenon. The liver biopsy revealed mononuclear cell infiltration with fibrosis in the portal area. These data indicated that she also had autoimmune hepatitis (AIH) and mixed connective tissue disease (MCTD). The analysis of human leukocyte antigen (HLA) showed positive A11 which had been reported to relate to Graves' disease, and positive DR4 which had been reported to relate to AIH and MCTD. These results suggested that HLA would determine susceptibility to three distinct autoimmune diseases in this case.

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We herewith report a case of amyloid goiter secondary to Crohn's disease. The patient had been diagnosed as having Crohn's disease at the age of 15, and underwent right hemicolectomy at age 20. When he was 26 years old he complained of swelling of the anterior neck. Both TSH and thyroid hormones were within the normal range, and anti-thyroglobulin and anti-microsomal antibodies were negative. Only thyroglobulin was noticeably above the normal range. During the next year his goiter enlarged further and because he had a feeling of pressure he underwent total thyroidectomy. The presence of amyloid A protein in his surgical specimen led to the diagnosis of amyloid goiter. Although most cases of secondary amyloidosis are known to develop in neoplasms or chronic inflammatory diseases, our patient had no illness other than Crohn's disease. Perusal of literature revealed that Crohn's disease is rarely a cause of amyloid goiter.

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A three-month-old boy presented congenital hypopituitarism in which the hypothyroid state masked ACTH deficiency. Multiple anterior pituitary hormone deficiencies, including ACTH, were finally confirmed. High basal serum cortisol levels (up to 45.1μg/dl) were observed during a stressful episode before L-thyroxine replacement therapy was started. Decreased morning serum cortisol levels (5.0μg/dl or below) were observed on the sixth day of L-thyroxin replacement therapy despite mild hypoglycemia (lowest serum glucose level of 50mg/dl). ACTH deficiency was then confirmed by insulin-induced hypoglycemia test (peak serum cortisol level of 4.9μg/dl). The present findings showed that serum cortisol levels can be high during a stressful episode in an infant with ACTH deficiency and a coexisting hypothyroid state. Thus, the diagnostic evaluation of adrenal function soon after L-thyroxine replacement therapy is important in order to verify a possible subclinical ACTH deficiency, even in the presence of high serum cortisol levels before L-thyroxine replacement therapy.

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We describe a 48-year-old female with acute onset of central diabetes insipidus followed by mild anterior pituitary dysfunction. Magnetic resonance imaging (MRI) revealed enlargement of the hypophysis-infundibulum accompanied by a cystic component. She underwent a transsphenoidal exploration of the sella turcica. Histological examination showed foreign body type xanthogranulomatous inflammation in the neurohypophysis which might have been caused by rupture of a Rathke's cleft cyst. The MRI abnormalities and anterior pituitary dysfunction improved after a short course of corticosteroid administration, but the diabetes insipidus persisted. The histological findings in this case indicated the site of RCC rupture and the direction of the progression of RCC induced neurohypophysitis and adenohypophysitis.

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Acromegaly is a disorder caused by excessive secretion of human growth hormone (GH). Somatostatin and its analogue-prolonged release formulation, lanreotide (Somatuline PR), inhibit the secretion of growth hormone. The aim of this open Phase III study was to investigate the clinical efficacy of lanreotide in the treatment of six acromegalic patients with a mean age of 44±13yr including two patients with diabetes mellitus. All the patients previously received transsphenoidal or transcranial hypophysectomy. Lanreotide was given intramuscularly every 2 weeks at a fixed dose of 30mg for 12 weeks. Serum GH and insulin-like growth factor-I (IGF-I) levels were evaluated before, 2, 6 and 12 weeks after treatment. After 12 weeks of treatment, mean (±SEM) GH levels decreased from 24.8±12.5 to 6.9±3.3ng/ml and mean serum IGF-I levels decreased from 689±282 to 430±216ng/ml. Abdominal ultrasonographic examinations showed no gallbladder stone or bile sand formation before or after the treatment. Three of the patients who did not receive octreotide presented with manifestations of mild gastrointestinal adverse effect such as mild abdominal pain and diarrhea. In conclusion, lanreotide is effective in the treatment of active postoperative acromegaly.

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RET is a receptor tyrosine kinase expressed in neuroendocrine cells and tumors. RET is activated by a ligand complex comprising glial cell line-derived neurotrophic factor (GDNF) and GDNF receptor-α (GDNFR-α). Activating mutations of the RET proto-oncogene were found in multiple endocrine neoplasia (MEN) 2 and in sporadic medullary thyroid carcinoma and pheochromocytoma ofneuroendocrine origin. Mutations of the RET proto-oncogene and the glial cell line-derived neurotrophic factor (GDNF) gene were examined in human pituitary tumors. No mutations of the RET proto-oncogene including the cysteine-rich region or codon 768 and 918 in the tyrosine kinase domain were detected in 172 human pituitary adenomas either by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) or by PCR-restriction fragment length polymorphism (RFLP). Further, somatic mutations of the GDNF gene in 33 human pituitary adenomas were not detected by PCR-SSCP. One polymorphism of the GDNF gene at codon 145 of TGC or TGT was observed in a prolactinoma. The RET proto-oncogene message was detected in a normal human pituitary gland or 4 of 4 human pituitary adenomas with reverse transcription (RT)-PCR, and in rodent pituitary tumor cell lines with Western blotting. The expression of GDNF gene was detected in 1 of 4 human somatotroph adenomas, 1 of 2 corticotroph adenomas, and 2 of 6 rodent pituitary tumor cell lines with RT-PCR. Based on these, it is concluded that somatic mutations of the RET proto-oncogene or the GDNF gene do not appear to play a major role in the pituitary tumorigenesis in examined tumors.

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Although the mortality rate associated with papillary microcarcinoma (PMC) of the thyroid generally is very low, some patients present with bulky nodal metastasis or distant metastasis and have an unfavorable prognosis. We retrospectively reviewed clinical aspects, surgical treatment and outcome of 178 patients with PMC in an attempt to determine the prognostic factors. The cause-specific 10-year survival rate was 96%. Three of four patients who showed signs of distant metastasis during the postsurgical period died of the disease, and another died of local recurrence. The most significant prognostic factors were the presence of clinically apparent lymph-node metastasis and hoarseness due to recurrent nerve palsy at the time of diagnosis. All distant metastases and cancer-specific deaths occurred in the 30 patients with symptomatic PMC who had either cervical lymphadenopathy, recurrent laryngeal nerve palsy or both. The 148 patients who had neither symptom had a distinctily favorable outcome. Total thyroidectomy followed by radioactive iodine treatment did not improve the final outcome in patients with symptomatic PMC. We conclude that patients with asymptomatic PMC can expect a truly favorable outcome, but some of those with symptomatic PMC may fall within a high-risk group of patients who do not benefit from aggressive treatment.

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In anovulatory patients ovulation is usually induced by clomiphene citrate (CC) or gonadotropin therapy, but in the case of polycystic ovary syndrome (PCOS), diagnosed by the presence of several micropolycysts in the ovaries and a high LH/FSH ratio in the serum, CC is only minimally effective, and side effects are often a problem with gonadotropin therapy. In the present study we administered a Chinese herbal medicine Sairei-to which appears to have a steroidal effect in anovulatory PCOS patients. As a result of the treatment, serum LH and the LH/FSH ratio significantly decreased (P<0.01) and the ovulatory rate was 70.6%. Serum testosterone levels were within normal limits before the treatment, and did not significantly change during the treatment. Sairei-to may therefore be useful for the treatment of anovulation in PCOS patients.

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In this study, 35 patients with euthyroid diffuse goiter and 35 patients with euthyroid nodular goiter were treated with Levothyroxine (L-T4) for six months. The aim was to evaluate the efficacy of treatment on thyroid and nodule volumes and to evaluate the correlation between volume changes and thyroglobulin levels. Serum thyroid hormones, TSH, thyroglobulin, thyroid and nodule volumes were measured at the initial visit and after 6 months. Radioactive iodine uptakes of the thyroid gland were evaluated before treatment. The mean decrease of thyroid volume at six months was about 20% (20.4± 8.8ml vs. 16±7.9ml, P<0.001) in patients with diffuse goiter. All patients with diffuse goiter showed some decrement in their goiter sizes. Thyroid nodules, in response to thyroid hormone treatment, showed a variable behavior. A reduction of 50% or more in volume was detected in 31% (11/35) of the patients. 54% of the patients (19/35) showed a 10-49% decrease in nodule volume. Five of the patients were found to be insensitive to the therapy. Their nodule volumes either increased or did not change during therapy. Free T4 and free T3 levels increased and TSH levels decreased with L-T4 treatment in all patient groups. Patients with higher TSH levels (within normal limits) showed more volume reduction in the diffuse goiter group. No uniform correlation was found between volume changes and thyroglobulin levels in either of the patient groups. In conclusion, suppressive thyroxine treatment is effective in reducing the size of the goiter, and nodules and thyroglobulin levels cannot be taken as an indicator of the efficacy of L-T4 therapy.

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4A syndrome is characterised by adrenocortical insufficiency, achalasia, alacrima, autonomic and other neurological abnormalities. We report an 18-year-old boy with 4 A syndrome and having all classical features of the disease including sensorimotor neuropathy. In addition, the patient had low aldosterone levels and signs of osteoporosis, which apparently developed without glucocorticoid replacement therapy. Although it is speculated that the lack of local growth factors, nutritional deficiency secondary to achalasia or receptor abnormalities regarding bone metabolism contribute to osteoporosis, its etiopathogenesis still needs to be clarified.

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