Unusual presentations with bone, lung or soft tissue metastases in initial diagnosis of follicular thyroid carcinoma have been reported occasionally. This implies how difficult it is to diagnosis this type of cancer at the pre-operative or intra-operative stage of treatment. Fine needle aspiration cytology has been shown to be an ineffective method for diagnosing vascular or capsule invasion of follicular thyroid cancer. Multiple frozen sections, usually 5 to 12 depending on the size of the tumor, can achieve a diagnostic accuracy of 98%. Clinical application of various gene expressions in thyroid follicular tumors by needle aspiration using in situ hybridization requires further investigation. Although radioactive iodide (¹³¹I) has been used as the standard treatment for follicular thyroid carcinoma with distant metastases, the effectiveness of ¹³¹I treatment for follicular thyroid carcinoma depends on the differentiation of cancer cells. The possibility of ¹³¹I for thyroid remnant ablation replacing a secondary operation for follicular thyroid carcinoma has been debated. Recent studies applied more expressions of sodium iodide symporters to attain the effect of ¹³¹I treatment and slow the proliferation of thyroid cancer cell which, in turn, slows the progression of follicular carcinoma. Consensus for the surgical procedures for the specific prognostic risks for follicular thyroid carcinoma is needed. Dedifferentiated, anti-angiogenic, or gene therapies for follicular thyroid cancer with distant metastases or anaplastic transformation comprise the principal directions in future research for this cancer.

View full abstract

In animal experiments, adrenal cortical tissue has been successfully regenerated through xenotransplantation of cloned adrenocortical cells, suggesting that the intraadrenal stem cells required for such tissue formation may be present in the adrenal cortex. Stable expression of Ad4BP/SF-1, a key factor for adrenal and gonadal development and steroidogenesis, has been shown to direct embryonic stem cells toward the steroidogenic lineage. However, this steroidogenic capacity was very limited since progesterone was only produced in the presence of an exogenous substrate. Bone marrow mesenchymal cells are thought to contain pluripotent progenitor cells, which differentiate into multiple lineages. We have demonstrated that adenovirus-mediated forced expression of SF-1 in long-term cultured bone marrow cells can produce steroidogenic cells with the capacity for de novo synthesis of various steroid hormones in response to ACTH. This discovery may represent the first step in autologous cell transplantation therapy for patients with steroid hormone deficiency.

View full abstract

A pregnant 26-year-old woman was referred for evaluation and management of progressive hypertension and hypokalemia at 14 weeks of gestation. Her plasma aldosterone level was markedly elevated and magnetic resonance imaging showed a right adrenal tumor. Primary aldosteronism due to an aldosterone producing-adenoma was diagnosed. Because of progressive severe hypertension, a laparoscopic adrenalectomy was performed at 17 weeks of gestation. The procedure was completed without complication, and plasma aldosterone and potassium levels rapidly improved post-operatively. However, her hypertension persisted and the growth retardation of the fetus was found. Regrettably, intrauterine fetal death was confirmed at 26 weeks of gestation. Histological examination of the placenta revealed that the placental artery had very thick walls which had apparently caused a critical failure in fetal blood flow. The optimal timing of laparoscopic surgery during pregnancy and perioperative management were subsequently discussed.

View full abstract

Prediction of remission is one of the main problems of antithyroid drug (ATD) therapy for Graves' disease especially in patients who are treated with a minimum maintenance dose of ATD. We evaluated the ability of new sensitive TSH receptor antibody (TRAb) assays to predict remission in Graves' patients using two commercially available kits (TRAb-CT from Cosmic Corporation and TRAb-Dyno from Yamasa Corporation), compared to the original PEG assay. When a euthyroid state was achieved for more than 6 months with methimazole 5 mg/day or propylthiouracil 50 mg/day and thereafter for three months with 5 mg every other day or 50 mg every other day, respectively, we discontinued ATD medication. One year of observation after discontinuation of ATD was completed in 71 patients (60 females, median age 43 years, range 18-71), and TRAb values from these patients were analyzed in relation to prognosis. Twenty-six (37%) of the 71 patients had relapse of thyrotoxicosis and 45 remained euthyroid. The median TRAb levels in the relapse group were significantly higher than those in the remission group (P<0.05). Relapse occurred in 15/51 patients negative by TRAb-CT, in 11/20 patients positive by TRAb-CT (χ² = 4.1; P<0.05), in 11/42 patients negative by TRAb-Dyno and in 15/29 patients positive by TRAb-Dyno (χ² = 4.8; P<0.05). By contrast, relapse occurred in 23/64 patients with negative TRAb by PEG assay and in 3/7 patients with PEG assay positive values (n.s.). All patients with TRAb-CT values of 30% inhibition or greater, or TRAb-Dyno values of 3.0 U/L or greater relapsed during the observation period. Thus, measurement of TRAb by the new sensitive assays is useful for prediction of remission in our patients.

View full abstract

CD8⁺CD25⁺-activated cytotoxic T cells and anti-thyroglobulin antibodies (TgAb) are independently involved in the severity of Hashimoto's disease (HD). Interferon γ (IFN-γ) activates cytotoxic T cells. To evaluate the hypothesis that the functional +874A/T polymorphism in the gene encoding IFN-γ is associated with the severity of HD, we examined the frequencies of this polymorphism in 34 HD patients who developed hypothyroidism (severe HD); 22 untreated, euthyroid HD patients (mild HD); 49 patients with intractable Graves' disease (GD); 16 GD patients in remission; and 57 healthy volunteers. Frequency of the +874T allele, which is associated with high IFN-γ production, was higher in patients with severe HD than in those with mild HD (odds ratio [OR], 3.5; 95% confidence interval [CI], 1.0-12.4; p = 0.047), but there was no difference in the frequency between GD patients. The difference in the frequency of +874T was observed in the subset of patients with HD negative for TgAb (OR, 8.4; 95% CI, 1.2-57.3; p = 0.029) but not in the subset of patients with HD positive for TgAb. Our data indicate that the +874A/T polymorphism in the IFN-γ gene is associated with severity of HD.

View full abstract

This study is planned to investigate the role of ghrelin in normal variant short stature. Serum ghrelin, IGF-I and IGFBP-3 levels were measured in 17 children with constitutional delay of growth, 19 children with familial short stature and 11 age matched healthy children. Mean bone age of the constitutional delay of growth group was lower compared to other groups. Constitutional delay of growth group had lower mean weight compared to the controls. Serum IGF-I values were lower in the constitutional delay of growth group compared to the familial short stature and control groups. IGFBP-3 levels of the groups were similar. Ghrelin levels were higher in the short stature groups compared to the controls. In the multiple regression analyses, weight (β = –.54, p<0.0001) and height SDS (β = –.33, p = 0.01) were the independent determinants of ghrelin. The results of this study, the first one in which ghrelin levels are investigated in normal variant short stature, suggest that ghrelin does not play a role as a cause, but as a consequence in these patients because it is negatively correlated with weight and height standard deviation score. These negative correlations can be attributed to the compensatory response of ghrelin, which deserves further attention in future studies.

View full abstract

This study was performed to investigate the effect of androgen on the metabolism of bisphenol A (BPA), an endocrine disruptor, in order to clarify the mechanism of the higher levels of serum BPA in men and hyperandrogenemic women compared with normal women. Castrated female rats (OVX) were subcutaneously injected with testosterone propionate (TP) (0.01, 0.1, and 1 mg) every day for 2 weeks. Serum BPA concentrations in OVX rats showed a TP dose-dependent increase and were significantly higher at 0.1 and 1.0 mg of TP. The enzyme reaction of BPA glucuronidation in the rat liver microsomes showed that the ratio of glucuronide in the OVX rats was significantly reduced in a TP dose-dependent manner. Analysis of the mRNA expression of UDP-glucuronosyltransferase 2B1 (UGT2B1) by real-time quantitative RT-PCR revealed that the relative expression level of UGT2B1 mRNA showed a TP dose-dependent decrease. The results of enzyme analyses demonstrated that the ratio of BPA glucuronidation and the expression level of UGT2B1 mRNA were significantly lower under the hyperandrogenemic conditions. The clearance of BPA may be slowed in a TP dose-dependent manner, resulting in an increase of serum BPA concentration under hyperandrogenemic conditions.

View full abstract

In this study we evaluated the effect of a dual blockade with enalapril and losartan on the reduction of overt macroproteinuria and its potential mechanism(s) in hypertensive patients with type 2 diabetes. Twenty-six hypertensive patients with type 2 diabetes at the baseline were administered 5 mg of enalapril once daily for 12 weeks. At the beginning of the study, the subjects were assigned to receive an add-on of 50 mg of losartan once daily or 5 mg of enalapril once daily for another 12 weeks. Blood samples were collected at the baseline, at the beginning, and at the end of the study for the measurement of laboratory parameters, and these data, including blood pressure, were compared between the two groups. Treatment with 5 mg of enalapril significantly decreased the systolic blood pressure level in both groups, and the addition of losartan and/or enalapril further decreased the levels. There was no difference in blood pressure between the two groups. However, the addition of losartan, but not enalapril, significantly decreased the urinary protein excretion level, plasma aldosterone, and hypersensitive-C-reactive protein at the end of the study. The results established that the dual blockade of angiotensin II with enalapril and losartan has a greater clinical benefit for high-risk patients with hypertension and advanced diabetic nephropathy.

View full abstract

The prevalence of hypovitaminosis D has been recently reevaluated, and diabetes is considered as a risk factor for osteoporosis. We studied the association of the prevalence of hypovitaminosis D with the clinical features of diabetes. We conducted the observational study in 581 Japanese patients with type 2 diabetes mellitus and 51 normal subjects, and analyzed the relationship between serum 25-hydroxyvitamin D (25-OHD) concentration and the clinical features associated with type 2 diabetes. Mean serum 25-OHD concentration in type 2 diabetes patients was 17.0 ± 7.1 ng/ml (Mean ± SD) in winter, and was not statistically different from normal population (17.5 ± 3.6 ng/ml). The prevalence of hypovitaminosis D (<20 ng/ml) was 70.6%. Serum concentrations of 25-OHD were associated with HbA1c (P = 0.013), age (P = 0.070) and serum albumin (P<0.001), but were not related to BMI or the duration of diabetes. The levels of 25-OHD were significantly lower in the population with apparent microvascular complications, although serum creatinine levels were below 2.0 mg/dl. Serum 25-OHD concentrations in the group treated with insulin (15.4 ± 6.5 ng/ml) was lower than those in the patients treated with diet alone (20.8 ± 7.6 ng/ml) and with oral hypoglycemic agents (17.3 ± 7.0 ng/ml). Furthermore, the highest incidence of osteoporotic fracture and/or back deformity was observed in insulin-treated patients with hypovitaminosis D. In conclusion, these results suggest that microvascular complications and insulin treatment in type 2 diabetes patients are associated with the co-existence of hypovitaminosis D, and that hypovitaminosis D in insulin-treated patients is possibly related to the risk of osteoporotic fracture.

View full abstract

A major earthquake (Richter scale magnitude 6.8) struck the Chuetsu district of Niigata Prefecture, Japan, a rural area with mountain villages, on October 23, 2004. Strong aftershocks (Grade 5-6 on the Japanese intensity scale, JIS) continued for 2 months. We analyzed the earthquake's impact on 229 patients with various endocrine disorders [6 central diabetes insipidus (CDI), 16 adrenal insufficiency (AI) including 5 panhypopituitarism, 10 ACTH isolated deficiency and 1 Addison's disease, 145 Graves' disease and 62 Hashimoto's disease]. The status of patients with CDI or AI was not adversely affected by the earthquake. Twenty-eight (19%) patients with Graves' disease developed more severe hyperthyroidism; the incidence of developing more severe hyperthyroidism increased with greater degrees of hyperthyroidism. Three (5%) patients with Hashimoto's disease developed increased TSH concentrations. Most patients stayed in their own houses following the first shock. The median PTSD total score for all patients was low. However, the PTSD total score in patients with CDI or Hashimoto's disease was significantly higher than in other patients, while the subscore of mental status in patients with AI was significantly much lower than in other patients. In patients with Hashimoto's disease, patients whose hypothyroidism worsened had higher total and environmental effects score than patients whose hypothyroidism remained stable. Comparing patients whose hyperthyroidism became more severe to those in whom it remained stable, as well as on multiple logistic regression analysis, serum TRAb was found to be a risk factor for developing more severe hyperthyroidism. In conclusion, our findings indicate that Graves' disease patients need to maintain their euthyroid state with a low serum TRAb titer to prevent the development of further thyroid dysfunction after an earthquake, and that all patients should continue to take their medication, since it is likely that their lives will be interrupted by environmental effects owing to earthquake-shock, especially patients with CDI or Hashimoto's disease. Due to the risk of medical facility closure during a disaster, all patients should always have a note or copy of their medical records, including medical history and medications used, to avoid relying on patients remembering their drug names and doses. Furthermore, appropriate information should be provided by all means possible, including the mass media, to affected individuals, particularly those with AI, to decrease the occurrence of adverse consequences.

View full abstract

Multiple endocrine neoplasia (MEN) type 2B is a rare hereditary disorder characterized by medullary thyroid carcinoma, pheochromocytoma, and neuroma. Early signs of MEN 2B are usually neuroma, gastrointestinal problems, and medullary thyroid carcinoma. Noncardiogenic pulmonary edema is rare as a presenting symptom. We report a 31-year-old male who was admitted to our hospital because of noncardiogenic pulmonary edema. He was 168 cm in height, weighed 55 kg, and had an arm span of 166 cm. No marfanoid habitus was evident, but thickened lips and tongue neuroma were present. Chronic constipation had been present since childhood, and the patient had a two-year history of untreated hypertension. Noncardiogenic pulmonary edema and toxic megacolon were noted, and abdominal computed tomography revealed bilateral adrenal tumors. Ultrasonography of the thyroid showed two mass lesions. Intubation and mechanical ventilation were performed because of severe hypoxemia. Endocrinological examinations showed high levels of serum and urinary fractionated catecholamines, serum calcitonin, serum carcinoembryonic antigen, and serum intact parathyroid hormone. It was suggested that the high level of catecholamine from pheochromocytoma had caused the pulmonary edema. RET gene analysis showed a codon 918 mutation in exon 16 resulting in an ATG (methionine) to ACG (threonine) substitution, but analysis of the patient's parents showed the wild type. Therefore, the patient was diagnosed as having de novo MEN 2B. He underwent laparoscopic bilateral adrenectomy and total thyroidectomy. However, the values of serum calcitonin and CEA did not decrease to the normal ranges. Patients with early-stage MEN 2B have distinct characteristics that can aid early detection of the disease, thus possibly allowing them to be saved.

View full abstract

Although there are two types of amiodarone-induced thyrotoxicosis (AIT), only type II AIT has been seen at our institution in Japan so far. There have been few case reports of AIT recurrence, probably because of the fact that amiodarone is immediately discontinued once AIT has developed. Our own policy is not to discontinue amiodarone in all AIT patients, unless severe adverse effects such as pulmonary fibrosis develop. Among more than 50 patients with type II AIT we have encountered, three with arrhythmogenic right ventricular cardiomyopathy showed AIT recurrence. In these patients, the first episode of AIT developed 3, 4, and 2 years after the start of amiodarone administration, and recurrence was observed 5, 6, and 8 years after the first episode, respectively. The AIT resolved spontaneously in all cases while the patients continued to take amiodarone. In comparison with the first AIT episode, the second was milder and resolved within a shorter period. These three cases suggest that recurrence of type II AIT may not be rare in iodine-sufficient areas, and that it is relatively mild and may resolve spontaneously. Furthermore, at least in Japan, it may be possible for patients with recurrent type II AIT to continue taking amiodarone.

View full abstract

The purpose of this study carried out at a single institute in Japan was to investigate the clinical characteristics and complications of patients with adult growth hormone deficiency (GHD). Clinical and biochemical data of 110 patients (50 males, 60 females; mean age 42 ± 17 yr) with adult GHD who attended Tokyo Women's Medical University between 1990 and 1999 were analyzed retrospectively from medical records. This retrospective analysis demonstrated that 109 patients had multiple pituitary hormone deficiencies, with 98 patients having a deficiency of more than three hormones. Sixty-one patients had childhood onset GHD (COGHD) while the remaining 49 patients had adulthood onset GHD (AOGHD). Body mass index (BMI) ranged from 16.9 to 35.9 with a mean of 23.9 ± 4.1 (kg/m²), with BMI being ≥ 25 kg/m² in 38 patients (31% of COGHD and 38% of AOGHD). Forty-one percent of the patients had hypercholesterolemia, 41% had hypertriglyceridemia, 47% had decreased levels of HDL cholesterol and 48% had increased levels of LDL cholesterol. Intima-media thickness (IMT) of the carotid arteries was investigated in 33 patients, with abnormal findings including increased IMT or plaque being observed in 4 of 18 COGHD patients and 4 of 15 AOGHD patients. Diabetes mellitus and impaired glucose tolerance was found in 4 COGHD patients and 16 AOGHD patients. Insulin resistance was assessed in 36 patients by the homeostasis model insulin resistance index (HOMA-R) and ranged from 0.65 to 10.58 with a mean of 2.80 ± 0.37. This mean value of HOMA-R was significantly greater than that measured in normal subjects (1.58 ± 0.05: P<0.05). These data suggest that abnormal lipid and glucose metabolism, and atherosclerotic changes occur frequently in adult patients with GHD. Insulin resistance may play a role in glucose and lipid metabolism disorders associated with GHD.

View full abstract

Both peripheral innervation and nitric oxide (NO) participate in ovarian steroidogenesis. The purpose of this work was to analyse the ganglionic adrenergic influence on the ovarian release of steroids and NO and the possible steroids/NO relationship. The experiments were carried out in the ex vivo coeliac ganglion-superior ovarian nerve (SON)-ovary system of prepubertal rats. The coeliac ganglion-SON-ovary system was incubated in Krebs Ringer-bicarbonate buffer in presence of adrenergic agents in the ganglionic compartment. The accumulation of progesterone, androstenedione, oestradiol and NO in the ovarian incubation liquid was measured. Norepinephrine in coeliac ganglion inhibited the liberation of progesterone and increased androstenedione, oestradiol and NO in ovary. The addition of α and β adrenergic antagonists also showed different responses in the liberation of the substances mentioned before, which, from a physiological point of view, reveals the presence of adrenergic receptors in coeliac ganglion. In relation to propranolol, it does not revert the effect of noradrenaline on the liberation of progesterone, which leads us to think that it might also have a “per se” effect on the ganglion, responsible for the ovarian response observed for progesterone. Finally, we can conclude that the ganglionic adrenergic action via SON participates on the regulation of the prepubertal ovary in one of two ways: either increasing the NO, a gaseous neurotransmitter with cytostatic characteristics, to favour the immature follicles to remain dormant or increasing the liberation of androstenedione and oestradiol, the steroids necessary for the beginning of the near first estral cycle.

View full abstract

Adiponectin is an adipocyte-derived hormone involved in glucose, lipid and energy metabolism. A low plasma adiponectin concentration is associated with insulin resistance, obesity and atherosclerosis. In women, energy homeostasis is remarkably changed during gestation and lactation in order to supply sufficient nutrition for a fetus or newborn. In this study we aimed to elucidate the physiological impact of gestation and lactation on the plasma adiponectin levels and the influence of reproduction-related hormones on adiponectin secretion. We studied the longitudinal changes in plasma adiponectin concentration during pregnancy (1st, 2nd and 3rd trimester) and lactation (3 days and 1 month after the delivery) in lean healthy women (n = 22). The plasma adiponectin level declined slightly as the pregnancy advanced and reached its lowest level during lactation (12.25 ± 0.182 μg/ml at early pregnancy vs. 6.88 ± 0.375 μg/ml at 3 days postpartum, p<0.001). In order to investigate the role of the lactogenic hormone prolactin in the decrease of plasma adiponectin levels during lactation, we further performed in vitro experiments using human primary cultured adipocytes. Western blotting of the adipocyte lysate and ELISA of the culture medium revealed that exogenous prolactin inhibited both production and secretion of adiponectin in a dose-dependent manner. Our results thus suggests that prolactin affects the regulation of maternal metabolism through suppression of adiponectin.

View full abstract

A 75-year-old man with a medical history of autoimmune pancreatitis associated with autoimmune thrombocytopenia was emergently admitted to our hospital because of anorexia, vomiting, and transient loss of consciousness. Serum sodium was 115 mEq/l and the endocrinologic data indicated impaired secretion of ACTH, TSH, and gonadotropin, a preserved GH response, and increased PRL. Dynamic magnetic resonance imaging revealed marked swelling of the pituitary gland and stalk, with enhancement on early phase. The findings were consistent with lymphocytic hypophysitis according to the diagnostic criteria. Chest computed tomography revealed consolidation adjacent to the pleura in the right upper lobe, lower lobe, and left lower lobe. Because lymphocytic hypophysitis and associated organizing pneumonia were suggested, 50 mg of prednisolone was started and the dose was tapered. Swelling of the pituitary gland, lung lesion, and the LH and FSH response on the stimulation test were all markedly improved. Autoimmune pancreatitis, pituitary lesion, and organizing pneumonia might all be components of a systemic autoimmune fibrosclerosing disease in our case, although further studies are required to confirm this hypothesis.

View full abstract