The present review examines various reports describing prevalence of primary aldosteronism (PA) among hypertensives and the screening method of PA to better understand the current concepts used for diagnosing and managing PA among clinicians as well as specialists. Here, we describe and compare the prevalence of PA in Japan, which is well known to induce various vascular complications due to hyperaldosteronemia, resulting in cerebral infarction, myocardial infarction and renal failure, with that in another Asian area, US, European countries, Australia and Africa. The incidence rates for PA among hypertensives were recently reported to be widely raged between 3.2% and 20%. Those discrepancies are due in part to the completely different characteristics of the starting subjects used for studying the prevalence. Moreover, the criteria for screening PA among hypertensives, including aldosterone-renin ratio (ARR), and confirmatory tests for definitely diagnosing PA, such as saline infusion test are varied. We had already reported that a diagnosis of PA was made in 61 (6%) of the 1,020 hypertensive patients during the past five years, from 1995 until 1999. In our study, only 18% of the patients showed a serum K level of 3.3 mEq/l or less. Thus, many clinicians seem to misdiagnose PA as essential hypertension, because of absence of hypokalemia. Finally, we describe highlight key evidence for optimal methods for screening and definitely diagnosing PA among hypertensive patients in order to avoid misjudgment before or after treating hypertensive patients.

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Obesity is a rapidly increasing public health concern worldwide as a major risk factor for numerous disorders, including diabetes, hypertension and heart disease. Despite remarkable advances in obesity research over the past 10 years, the molecular mechanisms underlying obesity are still not completely understood. To maintain systemic energy homeostasis, it is important that organs/tissues communicate metabolic information among each other. Obesity-related disorders can be thought of as resulting from dysregulation of this inter-tissue communication. This system has both afferent sensing components and efferent effecter limbs. The afferent signals consist of not only humoral factors, such as nutrients (glucose, fatty acids and amino acids) and adipocytokines (leptin, adiponectin and so on), but also autonomic afferent nerve systems. Both converge on brain centers, most importantly within the hypothalamus, where the signals are integrated, and the direction and magnitude of efferent responses are determined. The efferent elements of this physiological system include those regulating energy inputs and outputs, i.e. food intake and metabolic rates. In this review, we will summarize recent advances in research on metabolic information avenues to the brain, which are important for energy homeostasis.

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Forkhead transcription factors of the FoxO family have important roles in cellular proliferation, apoptosis, differentiation and stress resistance. FoxO proteins also play important roles in metabolism of complex organisms. FoxO1 regulates glucose and lipid metabolism in liver, as well as preadipocyte, myoblast and vascular endothelial cell differentiation. In the hypothalamus, FoxO controls food intake. In this chapter, we review the role of FoxO in pancreatic β cells. Pancreatic β cells secrete insulin to maintain the plasma glucose levels in a strict physiological range. Defects of β cell function cause diabetes. The expression pattern of FoxO1 during pancreatic organogenesis is similar to that of Pdx1, Nkx2.2 and Pax4, transcription factors known to be critical for β cell development. FoxO1 is expressed in a subset of pancreatic duct cells, in which insulin and/or Pdx1 are occasionally expressed. FoxO1 inhibits β cell proliferation through suppression of Pdx1 by competing with FoxA2 and protects against β cell failure induced by oxidative stress through NeuroD and MafA induction. Thus, a series of FoxO1 studies in pancreas suggested that FoxO1 plays important roles in pancreatic β cell differentiation, neogenesis, proliferation and stress resistance. Genetic or pharmacological manipulation of FoxO can be used to prevent β cell failure or aid in the differentiation of uncommitted endocrine progenitors into β cells for transplantation.

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Fructose 2,6-bisphosphate (F2,6BP) is a powerful allosteric activator of 6-phosphofructo-1-kinase, which is the rate-limiting enzyme for glycolysis. Mitogenic stimulation of lymphocytes is related to an enhanced rate of glucose utilization and F2,6BP mediated activation of glycolysis. To determine the effect of hyperglycemia on intracellular glycolysis of lymphocytes, we measured intracellular F2,6BP content in peripheral blood mononuclear cells obtained from patients with diabetes and normal subjects. A total of 62 subjects participated in the present study. Venous blood samples were collected and peripheral blood mononuclear cells were separated by Ficoll gradients. Intracellular F2,6BP levels in peripheral blood mononuclear cells from normal control subjects were significantly lower than age-matched diabetic subjects. We observed a significant positive correlation between intracellular F2,6BP levels and long term glycemic control, as assessed by HbA1c. These data suggest that hyperglycemia increases intracellular F2,6BP in immune cells. These findings may help to clarify the impaired function in immune cells in patients with diabetes.

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This study was conducted to evaluate the long term effect of castration on the prostate gland proliferation, extracellular matrix remodeling and angiogenesis. Prostate gland proliferation was assessed by immunolocalization of proliferating cell nuclear antigen (PCNA). The expression level of vascular endothelial growth factor (VEGF), transforming growth factor-β (TGF-β) and metaloprotenase-13 (MMP-13) by the prostate gland were assessed by immunohistochemistry and quantitative real-time PCR. The expression of the above mentioned parameters by the prostate gland of mature intact dogs were compared to that of castrated dogs six months post-castration. The results showed that castration induced a remarkable atrophy of the prostate gland which was associated with a highly significant decrease in the PCNA proliferation index. Although TGF-β protein was immunolocalized to the epithelial and stroma cells of the prostate gland from both intact and castrated dogs, castration induced a significant up-regulation of TGF-β mRNA expression. VEGF mRNA expression and its encoded protein immunolocalization were decreased significantly by the prostate gland from castrated dogs as compared to that of intact dogs. Castration, on the other hand, resulted in no significant change in MMP-13 mRNA expression despite an effect on its cellular immunolocalization which appeared to be localized to the epithelial and stromal cells of the prostate gland from castrated dogs as compared to epithelial cells of the prostate gland from intact dogs. These results indicated that castration-induced prostate gland regression continued to exert a potent suppressive effect on prostate gland proliferation which might be mediated by the elevated level of TGF-β. Moreover, the low expression level of VEGF might reflect a reduced blood flow demand by the regressed and growth-dormant prostate after castration.

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Since the majority of multiple endocrine neoplasia type 2A (MEN 2A) patients have missense mutations at codon 634 and those with the Cys630 RET genotype mutations are extremely rare, limited clinical information is available about this rare type. We report here three members of one Japanese MEN 2A family with the Cys630Tyr genotype. A 67-year-old woman presented a firm thyroid nodule, and preoperative examination revealed medullary thyroid carcinoma with primary hyperparthyoidism and no pheochromocytoma. At surgery, bilateral medullary thyroid carcinomas and parathyroid adenoma were found. No lymph node metastasis was identified. Computed tomography scans and laboratory examination of blood have shown no evidence of tumor recurrence and no abnormality of parathyroid function during the 4 years after surgery. A 40-year-old man, the proband's son, was shown to have the same RET mutation, underwent total thyroidectomy prophylactically, and only microscopic foci of medullary thyroid carcinoma were found. A 10-year-old boy, the proband's grandson also having the same RET mutation, showed normal basal serum calcitonin level and has been followed up conservatively. To our knowledge, 18 patients of 6 families with the Cys630 mutations have been reported so far. This is only the second reported case with primary hyperparathyroidism. RET 630 mutations might be associated with lower penetrance of primary hyperparthyoidism and pheochromocytoma.

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Acromegaly is caused by excessive secretion of growth hormone (GH), and a resultant persistent elevation of insulin-like growth factor-1 (IGF-1) levels. Diabetes mellitus is accompanied in some acromegalic patients with insulin resistance. We encountered a type-2 diabetic patient who had a poorly controlled glycemic state and was diagnosed as acromegaly with normal IGF-1 levels. The patient showed definite acromegalic features. However, in the first screening test, GH levels were high and IGF-1 levels were inappropriately normal so the results were not close to the diagnosis of acromegaly. After moderate glycemic control, an oral glucose suppression test was performed, showing no suppressed GH response. TRH test revealed paradoxical increases in growth hormone levels and a brain MRI discovered a pituitary adenoma. After several-months insulin treatment, IGF-1 levels were increased to the abnormal state and GH levels were decreased without treatment for acromegaly. Here we report the rare case of acromegaly that presents inappropriately normal IGF-1 levels at the time of diagnosis in uncontrolled type 2 diabetic patient and shows increased IGF-1 levels after glycemic control with insulin therapy. When evaluating acromegaly in type 2 diabetes under poorly controlled glycemia, cautious IGF-1 analysis is needed after sufficient glycemic control.

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A right adrenal tumor was incidentally discovered on abdominal computed tomography performed on a 53-year-old Japanese man, who had been hospitalized with diabetic ketoacidosis. Normal values were obtained for adrenal hormones in the morning after an overnight fast and urinary cortisol excretion after treatment of diabetic ketoacidosis with insulin. However, overnight dexamethasone administration with 1 mg or 8 mg did not completely suppress serum cortisol levels. There were no remarkable physical findings related to Cushing's syndrome. The patient was diagnosed as having preclinical Cushing's syndrome (PCS). Histological examination of the adrenalectomy specimen demonstrated adrenal black adenoma. Blood glucose levels subsequently improved after adrenalectomy, and the patient never developed adrenal insufficiency after hydrocortisone withdrawal. The patient was treated with diet therapy alone, and maintained good glycemic control. However, the patient still showed a diabetic pattern in an oral glucose tolerance test. It seems that the existence of PCS in addition to the underlying type 2 diabetes mellitus contributed to aggravation of blood glucose levels. Although there are many aspects of the natural course of PCS that have not been thoroughly elucidated, it is necessary to remain aware that a PCS patient with abnormal glucose metabolism may develop diabetic ketoacidosis by environmental agents.

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Adiponectin, an antiatherogenic peptide, has diverse biological actions on insulin sensitivity, inflammation and lipid metabolism. To explore physiological and pathophysiological significance of adiponectin in the Japanese general population, we systematically analyzed the relationship between adiponectin and high sensitive CRP (hsCRP), lipids, insulin sensitivity, and anthropometric parameters in 166 consecutive adult male health examinees. By univariate analysis, serum adiponectin was positively correlated with age and HDL-cholesterol, and inversely correlated with fasting plasma glucose, fasting insulin, homeostasis model assessment insulin-resistance, waist, body mass index, triglycerides and hsCRP. However, multivariate analysis revealed that adiponectin independently correlated with triglycerides (r = –0.243, P = 0.0033) and hsCRP (r = –0.262, P = 0.0015) but not with all other variables. Adiponectin was lower and hsCRP higher in the subjects with metabolic syndrome (n = 22) than in those without it (n = 144) (adiponectin, 5.4 ± 2.8 vs 7.5 ± 4.2 μg/ml, p = 0.002; hsCRP, 832 ± 605 vs 470 ± 524 ng/ml, p = 0.0004). Current findings suggest that relative importance of hypertriglyceridemia and enhanced inflammation, rather than insulin resistance, as the downstream events of hypoadiponectinemia leading to atherosclerosis in the Japanese general population.

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Riedel's thyroiditis is a rare form of chronic thyroiditis, characterised by a fibroinflammatory process that partially destroys the thyroid and often involves surrounding tissues. The relationship of Riedel's thyroiditis to other forms of thyroiditis is not clear. A case of Riedel's thyroiditis in a 51-year-old woman presenting with symptoms of subacute thyroiditis, is reported. She was diagnosed with subacute thyroiditis based on clinical manifestation and laboratory results. She was treated with glucocorticoids for six weeks, and then followed-up for 12 months. Three years later, she visited with tenderness and enlargement of thyroid mass, and laboratory and radiology findings suggested that she had a malignant thyroid tumor as well as subacute thyroiditis. After thyroidectomy, histopathologic findings showed that she had Riedel's thyroiditis in the presence of subacute thyroiditis. Until now, few cases of Riedel's thyroiditis in patients with a history of subacute thyroiditis have been reported in the literature. Although the etiology of Riedel's thyroiditis is unknown, it may develop in the course of subacute thyroiditis.

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Pregnant diabetic Wistar rats were fed a high-fat diet starting at the first gestational day. The effect of the high-fat diet on the growth of the female, her offspring, and the offspring's offspring was studied. Pregnant rats (first generation) were divided into the Diabetic streptozotocin-induced group and the control group. Diabetic streptozotocin-induced rats and control rats were fed either a control diet (5% fat in diet) or high-fat diet (32% fat in diet), and observed up to the third generation. In each generation, after weaning, the pups were fed the respective diet. The fat content was mainly animal lard. Diabetic rats fed the high-fat diet were infertile, and the pregnant first-generation and diabetic rats fed the control diet had a stillbirth rate of 27.5 ± 22.0% (mean ± SE). In the first generation, the diabetic rats fed the control diet had a significantly lower body weight increase during the pregnancy than the control rats fed the control diet. The second-generation diabetic rats fed the control diet had a high blood glucose level at birth, and their triglyceride level was higher than that in the other two groups. The third-generation diabetic rats fed the control diet had a triglyceride level higher than that of control rats. Delivery was most difficult in diabetic rats fed the high-fat diet. Pups of diabetic rats fed the control diet had growth retardation and increased blood glucose levels. We conclude that when the mother rat had diabetes, the next generation was also affected.

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To compare the pharmacokinetic and pharmacodynamic effects of glimepiride between once- and twice-daily dosing in type 2 diabetic patients. Eight Japanese type 2 diabetic patients, who had been treated with 2 mg glimepiride alone over 4 weeks (age 40-70, body mass index ≤25 kg/m², hemoglobin A_1C<8.0%), were randomly assigned to the crossover study with glimepiride 2 mg once-daily and 1 mg twice-daily for 4 weeks for each regime. Serum concentrations of glimepiride, plasma glucose, insulin and C-peptide were measured over 24 h at the fixed time intervals on the last day of each crossover period, and HbA_1C was measured at the same day. Pharmacokinetic profiles in two regimens were different to each others; a single peak of serum glimepiride concentration was observed in once-daily, and double peaks in twice-daily dosing. Drug concentration increased immediately, and peaked at 2 h after administration irrespective of dosage. Cmax value in once-daily dose was higher than those in twice-daily doses. AUC values were not different between two regimens. Pharmacodynamic profiles for plasma glucoses, serum insulin and C-peptide showed no statistically significant differences between two regimens, and parameters were not different each other. Analyses of adverse events and laboratory data demonstrated a favorable safety profile of glimepiride. The present results suggest that glimepiride may be suitable for once-daily dosing with respect to clinical usefulness.

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A 69-year-old woman was admitted for the treatment of marked pleural effusions and peripheral edema. Analytical studies of the pleural effusion revealed exudates. Culture for bacterial organisms and tuberculosis were negative, and cytology was normal. She had a mediastinal tumor at the age of 61 and regular follow-up showed no evidence of malignancy. She underwent the mediastinal tumor resection, because we thought this was the cause of her symptoms. However, her clinical symptoms persisted after surgery. Next, we noticed subclinical hypothyroidism, in which serum TSH level was elevated with concomitant normal thyroid hormone levels. In addition, serum vascular endothelial growth factor (VEGF) levels, which have been reported to be related to the pathophysiology of the extravascular volume overload, were elevated. Although her TSH level was slightly elevated (15.4 μU/ml), we started thyroid hormone replacement therapy. This therapy gradually ameliorated her clinical manifestation and abnormal laboratory data, including elevated VEGF levels. These observations indicate that even subclinical hypothyroidism may cause severe clinical manifestations. Furthermore, elevated VEGF may be a contributing factor in the pathogenesis of extravascular volume overload in hypothyroid patients.

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We investigated the regulation of each intracellular signal transduction system including cyclic AMP (cAMP)-dependent and calcium (Ca²⁺) messenger systems in bovine adrenal fasciculo-reticularis cells to clarify the exact mode of action of ACTH. Pretreatment with primaquine and quinacrine, which are phospholipase A₂ inhibitors, significantly inhibited cortisol production activated by both low and high concentrations of ACTH. Therefore, it seems that metabolites induced by phospholipase A₂ are quite essential for cortisol synthesis induced by ACTH, either at low or high concentrations. At low concentrations of ACTH (10^–13–10^–12 M), significant increases of cytosolic calcium ([Ca²⁺]_i), but not of cAMP, were observed. Calphostin C, a specific protein kinase C inhibitor, apparently suppressed cortisol production activated by low concentrations of ACTH, while H-89, a specific inhibitor of cAMP-dependent protein kinase, did not. These findings suggest that, at physiologically low concentrations, ACTH activates [Ca²⁺]_i and phospholipase A₂ without affecting cAMP formation, resulting in an increased biosynthesis of cortisol, partly via protein kinase C-dependent processes. At high concentrations, ACTH (10^–9–10^–7 M) induced an increase of cAMP and [Ca²⁺]_i. The cortisol production induced by high concentrations of ACTH was significantly inhibited by pretreatment with calphostin C, H-89 and H-7, suggesting the participation of cAMP-dependent protein kinase and protein kinase C systems in the regulation of cortisol production in the presence of high concentrations of ACTH. In conclusion, cytosolic calcium is biphasically enhanced by ACTH, although cAMP accumulation is increased only by high concentrations of ACTH. A phospholipase A₂-dependent process may partly play a crucial role in the regulation of cortisol biosynthesis, when stimulated by low and high concentrations of ACTH.

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Both increased and decreased fibrinolytic activity have been reported in patients with hyperthyroidism. Elevated levels of plasma plasminogen activator inhibitor-1 (PAI-1) antigen have been found in hyperthyroid patients. Thrombin activatable fibrinolysis inhibitor (TAFI) is a novel plasma protein, which inhibits fibrinolysis through removal of C-terminal lysines from partially degraded fibrin. Previously, we showed that plasma TAFI antigen levels were increased in patients with overt and subclinical hypothyroidism. The aim of this study is to investigate plasma levels of TAFI and PAI-1 antigens in hyperthyroid patients. PAI-1 and TAFI antigen levels were measured in the plasma of 29 patients with hyperthyroidism (14 overt hyperthyroid and 15 subclinical hyperthyroid), and 26 healthy individuals. Although there were increased levels of PAI-1 antigen in hyperthyroid patients, plasma TAFI antigen levels were significantly lower compared to controls (80.79 ng/ml vs. 32.42 ng/ml, p = 0.000 for PAI-1; 10.42 μg/ml vs. 12.24 μg/ml, p = 0.009 for TAFI). Elevated PAI-1 antigen levels were positively correlated with free thyroid hormones, although TAFI antigen levels were in negative correlation with free thyroxine. Furthermore, an inverse correlation between PAI-1 and TAFI antigen levels was found. Our study demonstrated that TAFI antigen levels were decreased in patients with hyperthyroidism. Inverse correlation with PAI-1 suggests that the decrease in TAFI antigen levels may be due to activation of TAFI pathway. Further studies evaluating the underlying mechanisms of low TAFI antigen levels in hyperthyroidism should be undertaken.

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Carbohydrate antigen 125 (CA125) is a tumor-marker frequently associated with ovarian malignancies; however, benign gynecologic conditions (e.g. ovarian cysts) commonly cause a smaller increase in CA125 levels. This report describes an elderly Japanese woman with high CA125 levels and massive ascites caused by hypothyroidism. A 67-year-old woman presented herself with a weight gain of about 12 kg and abdominal distension. Her serum CA125 level was markedly elevated (822 U/ml) and abdominal CT revealed a right ovarian cyst and massive ascites. Hormonal laboratory data showed severe primary hypothyroidism with a serum TSH of 594 IU/L and a free thyroxin level of 0.05 ng/dl. Ascitic fluid was found to be exudate with a high protein content of 42 g/L. Cytological analysis and FDG-PET showed no evidence of malignancy. The ascites completely disappeared and serum CA125 normalized after adequate hormonal replacement therapy. These data suggest that hypothyroidism should be considered in patients with ascites and elevated serum CA125.

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Monocyte adhesion to arterial endothelial cells is the initial step in atherosclerosis. Whereas angiotensin II is known to elicit leukocyte adhesion, it is not clear whether blockade of the angiotensin II receptor signaling reduces monocyte adhesion to endothelial cells beyond its antihypertensive action. This study compared the effect of two different antihypertensive drugs on monocyte adhesion to thoracic aorta endothelium in spontaneously hypertensive rats (SHR): the angiotensin II receptor blocker, valsartan (20 mg · kg^-1 · day^-1) and the vasodilator, hydralazine (0.75 mg · kg^-1 · day^-1). The effects were quantitated in vivo using an enface method that optimizes the observation of endothelial surfaces after immunohistochemical staining for CD68. Both agents significantly and comparably reduced blood pressure over 4-week treatment course. Both valsartan and hydralazine profoundly reduced monocyte adhesion compared with nontreated controls, with valsartan having a modestly more reductive effect. Both agents also reduced the intima and medial thickening with valsartan reducing the mean thickness modestly more than hydralazine. Our data confirms that the reduction of blood pressure is effective method to reduce monocyte adhesion. Also, our date demonstrates that valsartan has a modest beneficial effect on monocyte adhesion to endothelial cells and arterial intima-medial vessel thickening beyond its action as an antihypertensive agent.

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Endothelial dysfunction is an early marker of atherosclerosis. Pioglitazone is commonly used in the treatment of type 2 diabetes and has vascular protective effects beyond its hypoglycemic ones. We investigated the vascular effects of short-term, low-dosage pioglitazone in patients with type 2 diabetes. The study included 15 subjects with type 2 diabetes with normoalbuminuria (age, 60.7 ± 11.9 years; body mass index [BMI], 23.9 ± 3.3 kg/m²). The patients received pioglitazone at 15 mg daily for 4 weeks. BMI, systolic and diastolic blood pressure, laboratory parameters (fasting plasma glucose, insulin, lipid profile, high-sensitive C-reactive protein [hsCRP], and adiponectin) were assessed at baseline and after treatment. The forearm blood flow (FBF) was measured during reactive hyperemia by strain-gauge plethysmography. Short-term, low-dosage pioglitazone did not improve glycemic control or insulin sensitivity. However, the peak FBF and flow debt repayment (FDR) were markedly improved. There was no correlation of the improvement of peak FBF and FDR with the observed changes of metabolic parameters. However, the increment of adiponectin and decrement of hsCRP were well correlated with the improvement of peak FBF. These results indicate that short-term low-dosage pioglitazone may improve vascular function via increasing adiponectin expression and decreasing low-grade inflammation in type 2 diabetic patients.

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The measurement of TSH receptor antibody (TRAb) has been recommended to predict the risk of neonatal hyperthyroidism (NH) in pregnant women with Graves' disease (GD). For the first generation TRAb (TRAb1) assay with commercial kit (Brahms, Berlin, Germany; or Cosmic co., Tokyo, Japan) an arbitrary limit of 40 U/l or 50% was suggested to indicate risk when measured late in pregnancy. In order to substitute TRAb1 with the second generation TRAb using porcine TSH receptor (pTRAb2) and human recombinant TSH receptor (hTRAb2) and the third generation TRAb (TRAb3) assay for this purpose, we measured TRAb in these four methods late in pregnancy in a total of 62 pregnant women with Graves' disease. The data showed that no cases with TRAb1 >50% has been missed if the TRAb1 assay was replaced by the pTRAb2, hTRAb2 or TRAb3 assay using their equivalent cut-off value of 70%, 10 IU/l, and 75%, respectively, but that an additional group of women would have been included in the risk group, especially in the TRAb3 assay. Next, the effect of maternal TRAb on thyroid function of offspring was studied in the 47 pregnant women with GD (43 with TRAb1 <50% and 4 with TRAb1 >50% during late pregnancy). In 2 women who gave birth to hyperthyroid children at days 6 and 14 of life, the maternal sera had strongly positive levels of TRAb1 (73.5% and 84.1%), pTRAb2 (84.9% and 91.5%), hTRAb2 (40.68 IU/L and 89.70 IU/L) and TRAb3 (92.1% and 93.5%) late in pregnancy, with one case displaying high positive (1114.3%) thyroid stimulating antibody (TSAb) level and the other case had moderate positive (433%) TSAb level. Of the remaining 45 women, 43 had TRAb1 <50% and the other 2 had TRAb >50% including 1 with low TSAb positive and 1 with positive thyroid stimulating blocking antibody (TSBAb) and negative TSAb; all of them gave birth to euthyroid children. Finally, a serial study regarding TRAb in 23 women with Graves' disease during pregnancy showed that TRAb1, pTRAb2, hTRAb2, TRAb3 value and TSAb level decreased significantly as pregnancy progressed. In conclusion, the present study supported TRAb as a useful marker to predict the risk of NH.

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Recent findings suggest that thyroid stimulating hormone (TSH) is a negative regulator of skeletal remodeling by reducing both differentiation of osteoblasts and formation of osteoclasts. In addition, increased fracture risk in untreated hypothyroid patients has been reported to begin up to 8 years before diagnosis. The aim of the present study was to evaluate the effect of subclinical hypothyroidism on bone structure by using the heel QUS. Subjects were outpatients without any past or present history of thyroid disease. Among 210 postmenopausal women, 22 of 33 patients (Hypo), who had elevated serum TSH concentration (TSH≥4 μU/ml) with normal serum free thyroxine (FT₄) concentration, agreed to join to this study. We also randomly selected 24 control subjects (Cont) from 176 postmenopausal women with normal thyroid status. Calcaneus osteo sono assessment indices (OSI) of right feet were measured using the ultrasound bone densitometry AOS-100. Serum TSH concentrations in Hypo patients (5.31 ± 1.3 μU/ml) were higher than those in Cont patients (2.05 ± 1.1 μU/ml), and there was significant difference of FT₄ concentrations (Cont 1.33 ± 0.15 ng/dl; Hypo 1.19 ± 0.17 ng/dl). OSI and its Z-score in Hypo subjects (OSI, 2.138 ± 0.152; Z-Score -0.322 ± 0.504 SD, Mean SD) were significantly lower than those in Cont subjects (OSI, 2.347 ± 0.243; Z-Score 0.322 ± 0.91 SD, Mean ± SD). Simple regression statistical analysis showed that OSI decreased according to the increase of serum TSH concentration (n = 47, P<0.037). In addition, multiple regression analysis showed that the elevation of serum TSH concentration was associated with the decrease of OSI. These results suggest that the elevation of serum TSH concentration in subclinical hypothyroidism affects not bone turnover but bone structure as assessed by QUS.

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We describe here a case of reversible ampulla (takotsubo) cardiomyopathy caused by secondary adrenal insufficiency in ACTH isolated deficiency. A 53-year-old woman was referred to our department for evaluation and treatment of unconsciousness. On admission, her plasma glucose level was 34 mg/dL, suggesting loss of consciousness due to hypoglycemia. Basal levels of ACTH, cortisol, and dehydroepiandrosterone sulfate in blood, and urinary free cortisol levels were all decreased. ACTH and cortisol levels were not adequately increased in response to CRH administration and the insulin tolerance test. Electrocardiography showed ST segment elevation and T wave inversion in leads V_1-6. The coronary arteries were free of organic stenosis, and a left ventriculogram revealed severe hypokinesis, particularly in the anterior and posterior walls. Based on a diagnosis of adrenocortical insufficiency caused by ACTH isolated deficiency, hydrocortisone was administered. Two weeks after treatment, ultrasound studies of the heart showed recovery of left ventricular wall motion. Activation of the sympathetic nervous system, adrenocortical failure, and hypoglycemic attack were considered to be triggering factors for the takotsubo cardiomyopathy. Careful monitoring of cardiac function and appropriate treatments for both cardiomyopathy and adrenocortical failure are required to recover cardiac dysfunction.

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LIM homeodomain transcription factors regulate many aspects of development in multicellular organisms. LHX4/Lhx4 is a protein that is essential for pituitary development and motor neuron specification in mammals. In human, a heterozygous splicing mutation of the LHX4 gene was reported in a family with combined pituitary hormone deficiencies (CPHD). In addition to CPHD, these patients were characterized by small sella turcica and chiari malformation. Here we report a Japanese patient with CPHD (GH, PRL, TSH, LH, FSH, and ACTH deficiency) due to a novel missense mutation (P366T) of the LHX 4 gene. She showed severe respiratory disease and hypoglycemia soon after birth. Brain MRI demonstrated hypoplastic anterior pituitary, ectopic posterior lobe, a poorly developed sella turcica, and chiari malformation. Sequence analysis of the LHX 4 gene identified a heterozygous missense mutation (P366T) in exon 6, which was present in LIM4 specific domain. Neither of the patient's parents harbored this mutation, indicating de novo mutation.

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Water intoxication usually happens in patients with a psychiatric problem, who are subject to compulsive water ingestion, and during clinical examinations, such as uroflowmetry, and is seldom observed in ordinary people. Here we report a patient with severe hyponatremia due to voluntary water drinking coexisting with no psychiatric problems. The case presented clinically significant hyponatremia 124 mmol/L without any signs of dehydration after voluntary ingestion of 4000 ml of water over 3 hours. She normally responded to ingestion of 1000 ml of water over 20 min after recovery from hyponatremia, and did not meet the diagnostic criteria of SIADH. She was not a compulsive drinker. The present case suggests that one should consider water intoxication as a cause of hyponatremia in a patient without signs of dehydration, even if he/she does not have a history of compulsive water ingestion.

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