Controversy remains regarding the optimal dose calculation with radioiodine therapy for patients with Graves' disease. Here, we focused our analysis on data concerning the patient's pretreatment background, an empirically set dose of radioiodine and the post-treatment thyroid function, and investigated those factors that affected the outcome. The subjects consisted of 38 patients diagnosed as having Graves' disease. All patients were hospitalized to undertake radioiodine therapy between 1989 and 1998 at our hospital. At the follow-up periods of 6-, 12-, and 36-months after therapy, we divided the patients into two groups: one group those who had hypothyroid function, and the other those who had normal or hyperthyroid function. At 6- and 12-months, 50% of the patients belonged to the hypothyroid function group, whereas at 36-months, 55% of them had hypothyroid function. Logistic regression analysis, with the objective variable being the post-treatment hypothyroidism after 12 months, revealed that the significant factor was the onset age. We suggested that the age at onset should be considered in patients with Graves' disease to determine the optional radioiodine dose for the therapy.

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Impaired insulin secretion and insulin resistance are thought to be two major causes of type 2 diabetes mellitus. There are two kinds of diabetic model mice: one is a K_ATP channel knockout (Kir6.2KO) mouse which is defective in glucose-induced insulin secretion, and the other is a transgenic mouse expressing the tyrosine kinase-deficient (dominant-negative form of) human insulin receptor (hIR^KMTG), and which has insulin resistance in muscle and fat. However, all of these mice have no evidence of overt diabetes. To determine if the double mutant Kir6.2KO/hIR^KMTG mice would have diabetes, we generated mutant mice by crossbreeding, which would show both impaired glucose-induced insulin secretion and insulin resistance in muscle and fat. We report here that: 1) blood glucose levels of randomly fed and 6 h fasted double mutant (Kir6.2KO/hIR^KMTG) mice were comparable with those of wild type mice; 2) in intraperitoneal glucose tolerance test (ipGTT), Kir6.2KO/hIR^KMTG mice had an impaired glucose tolerance; and 3) during ipGTT, insulin secretion was not induced in either Kir6.2KO/hIR^KMTG or Kir6.2KO mice, while the hIR^KMTG mice showed a more prolonged insulin secretion than did wild type mice; 4) hyperinsulinemic euglycemic clamp test revealed that Kir6.2KO, Kir6.2KO/hIR^KMTG and hIR^KMTG mice, showed decreased whole-body glucose disposal compared with wild type mice; 5) Kir6.2KO, but not Kir6.2KO/hIR^KMTG mice had some obesity and hyperleptinemia compared with wild type mice. Thus, the defects in glucose-induced insulin secretion (Kir6.2KO) and an insulin resistance in muscle and fat (hIR^KMTG) were not sufficient to lead to overt diabetes.

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The activation of the growth hormone (GH) receptor is followed by activation of the JAK2-STAT system in peripheral tissues, which in turn induces the expression of suppressors of cytokine signaling (SOCS) and/or cytokine-inducible SH2 protein (CIS) to achieve the attenuation of the signaling. To examine whether GH involves the SOCS/CIS system as intracellular negative regulators in the hypothalamus, we observed the effects of human GH on the gene expression of SOCS/CIS in the rat hypothalamus. The mRNAs of CIS, SOCS2, and SOCS3 in the hypothalamus of hypophysectomized male rats were examined by Northern analysis following the intravenous administration of recombinant human GH (hGH), 50 μg/100 g BW. The SOCS3 and CIS mRNAs were increased transiently with maximum expression at 1 h after hGH administration. The intravenous hGH did not induce SOCS2 mRNA expression in the hypothalamus. In situ hybridization demonstrated the increase of SOCS3 and CIS mRNAs in the arcuate nucleus after hGH administration, and the increase of SOCS3 mRNA in the periventricular nucleus. The hGH applied to primary cultured hypothalamic neurons at 500 ng/ml induced transient increase of SOCS3 and CIS mRNAs, but not SOCS2 mRNA. The results show that hGH acts directly on the neurons in the hypothalamus, and increases SOCS3 and CIS mRNAs, suggesting that these negative regulators may be involved in the mechanism that turns off the hGH action in the hypothalamic neurons.

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Endobronchial metastases (EBM) are frequently seen in breast, renal and colon carcinomas. However, to our knowledge, only one case has ever been reported as EBM secondary to Hurthle cell carcinoma (HCC) in the literature. A 57-year-old woman had a bilateral total thyroidectomy for thyroid mass in 1990 that was diagnosed as HCC. She was admitted to our outpatient clinic in August 1999, with symptoms of cough, sputum, and right-sided pleuritic pain for the last seven months. In the bronchoscopic examination, two endobronchial lesions were seen. Pathological evaluation of the bronchoscopic samples was diagnosed as "Hurthle cell carcinoma" of thyroid. We suggest that, although rare, HCC should be considered in the differential diagnosis of the endobronchial metastasis.

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Skin collagen content and bone mass decrease with aging. Loss of collagen from the skin might decrease its elasticity. We investigated associations between skin elasticity, bone mineral density (BMD), age, and menopausal hypoestrogenism. Thirty-eight healthy Japanese postmenopausal women were studied (mean age, 55.7 ± 5.9 yr; range, 48 to 71). Skin elasticity was measured using a suction device applied to the dorsal right forearm. BMD values of L2 to 4 vertebral bodies were measured by dual-energy X-ray absorptiometry. Age showed significant negative correlations with both skin elasticity and BMD (r = –0.57, p<0.001 and r = –0.40, p<0.05, respectively). Years since menopause also showed significant negative correlations with both skin elasticity and BMD (r = –0.51, p<0.01 and r = –0.41, p<0.05, respectively). We also found a positive correlation between skin elasticity and BMD in these postmenopausal women (r = 0.44, p<0.01). In conclusion, we demonstrated declining skin elasticity and bone mass in postmenopausal women to possibly be age- and estrogen-related. Additionally, decreased skin elasticity might serve as a predictor of bone loss in postmenopausal women.

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This study was performed to investigate the serum levels of bisphenol A (BPA), an endocrine disruptor, in women with ovarian dysfunction and obesity. Fasting serum samples were obtained from 19 non-obese and 7 obese women with normal menstrual cycles: 7 patients with hyperprolactinemia, 21 patients with hypothalamic amenorrhea, and 13 non-obese and 6 obese patients with polycystic ovary syndrome (PCOS). BPA was measured by an enzyme-linked immunosorbent assay. BPA was detected in all human sera. Serum BPA concentrations were significantly higher in both non-obese and obese women with polycystic ovary syndrome (1.05 ± 0.10 ng/ml, 1.17 ± 0.16 ng/ml; p<0.05, respectively) and obese normal women (1.04 ± 0.09 ng/ml, p<0.05) compared with those in non-obese normal women (0.71 ± 0.09 ng/ml). There was no difference among women with hyperprolactinemia, women with hypothalamic amenorrhea, and non-obese normal women. There were significant positive correlations between serum BPA and total testosterone (r = 0.391, p<0.001), free testosterone (r = 0.504, p<0.001), androstenedione (r = 0.684, p<0.001), and DHEAS (r = 0.514, p<0.001) concentrations in all subjects. These findings show that there is a strong relationship between serum BPA and androgen concentrations, speculatively due to the effect of androgen on the metabolism of BPA.

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The present study was performed to record the electrical activity of olfactory placode neurons and to check the effect of GABA and bicuculline on it. Olfactory placodes obtained at day 13.5 of gestation were cultured for 1 week on multi-electrode dishes. Olfactory placode neurons showed spontaneous firing, with firing rates of 0.77 ± 0.05 Hz (0.03–3.82 Hz, n = 12), but there was no bursting activity. Perfusion with 10 μM GABA almost immediately inhibited 8 of 11 firing activities (we could not test it in 1 activity). In contrast, perfusion with 10 μM bicuculline induced facilitation in 5 of 12 activities and did not induce any change in 7 other activities. Statistical analysis by χ²-test showed a significant difference in the response of neurons to the two drugs. Fisher's exact probability test showed that the inhibitory effect of GABA was significant (p<0.05) whereas neither the facilitatory effect nor the lack of effect of bicuculline was significant (p>0.1). These results suggest that cultured olfactory placode neurons, even in a probably immature stage, respond to GABA with inhibition, as generally observed at mature stages.

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Maternal plasma leptin concentration is significantly increased during pregnancy. However, its roles in pregnancy, especially in labor, have not been fully clarified. We measured plasma leptin concentrations in pregnant women during the course of induced labor, just after spontaneous vaginal delivery and Cesarean section at term. We also studied the regulation of leptin secretion from term placental tissue and BeWo cells, a trophoblastic cell-line. Plasma leptin concentrations increased significantly during labor (58.9 ± 9.2 ng/ml) compared to those before labor induction (37.5 ± 5.8 ng/ml, P<0.05), then decreased 3–6 days postpartum (14 ± 3 ng/ml, n = 6, P<0.0001) to the levels of normal nonpregnant women. Leptin concentrations within an hour and 24 hours after spontaneous vaginal delivery were significantly higher than those after Cesarean section (P<0.05 for both comparisons). Similarly, leptin mRNA expression in placental tissues obtained after spontaneous vaginal delivery was significantly greater than that in those obtained after Cesarean section without labor (P<0.05). IL-1α and TNF-α treatment significantly stimulated leptin secretion and leptin mRNA expression in explant culture of human term placental tissue and in BeWo cells as compared with those in vehicle controls (P<0.05, for all comparisons). By contrast, oxytocin and prostaglandin F_2α treatment had no effects on leptin secretion from explant culture of human term placental tissue or from BeWo cells. These data indicate that pro-inflammatory cytokines might stimulate placental leptin secretion, thus finally contributing to the increase in plasma leptin concentration during labor.

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We describe two male pubertal cases of constitutionally tall stature (CTS) with an enlarged pituitary gland or pituitary microadenoma. Both patients' basal serum growth hormone (GH) levels were normal. Neither had oversecretion of any other pituitary hormones. However, their serum GH levels were paradoxically increased in response to an intravenous administration of thyrotropin-releasing hormone (TRH). A later GH response to an intravenous administration of luteinizing hormone-releasing hormone (LHRH) was also found in one patient. In addition, oral glucose loading (OGL) caused a late increase in serum GH at 180 min in both patients. Our present findings suggest that endocrinological and morphological abnormalities of the pituitary gland are found in some subjects with CTS during puberty. It is speculated that these paradoxical GH responses are associated with dysregulation of GH secretion. Finally, it is important to investigate whether tall children with morphological abnormalities of the pituitary gland such as our patients are preacromegalic, in which case, given that overproduction of GH secretion may occur in the future, further observation is necessary.

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Although gonadal estrogens are known to facilitate the development of skeletal lesion in SHOX haploinsufficiency, controversy exists as to whether gonadal estrogens are disadvantageous to pubertal growth. To clarify this matter, we analyzed growth pattern in 31 Japanese patients with a normal karyotype and molecularly confirmed SHOX haploinsufficiency. The mean height SD score at the diagnosis of SHOX haploinsufficiency was similar between patients identified in childhood and those identified in adulthood (–2.7 ± 0.8 [n = 15] vs. –2.4 ± 0.7 [n = 16], P = 0.36), and was significantly lower in patients identified by the studies for short stature than in those ascertained by the familial studies of the probands both in childhood (–3.0 ± 0.6 [n = 11] vs. –1.8 ± 0.5 [n = 4], P = 0.0051) and in adulthood (–3.0 ± 0.9 [n = 5] vs. –2.2 ± 0.5 [n = 11], P = 0.040). Analysis of longitudinal paired growth data obtained in seven females showed a significantly different mean height SD score between childhood and adulthood (–2.3 ± 0.5 vs. –2.9 ± 0.8, P = 0.0060). The results imply that gonadal estrogens have a deleterious effect on pubertal growth in SHOX haploinsufficiency, and that the growth disadvantage is recognizable by longitudinal rather than cross-sectional growth studies.

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We report a 45-year-old woman with Cushing's syndrome showing reversible pituitary dysfunction. Left adrenal tumor was incidentally discovered by a screening examination of abdominal computed tomography. Although this patient lacked typical Cushingoid features except hypertension and leg edema, endocrine examinations revealed moderate suppression of plasma ACTH (~6.3 pg/ml) with relatively high levels of serum cortisol (~22.9 μg/dl) without normal circadian rhythm. Plasma ACTH failed to respond to either CRH or metyrapone, and dexamethasone failed to suppress her daily steroid production. Surgical removal of left adrenocortical adenoma and 6-month replacement of hydrocortisone have ameliorated both ACTH and cortisol responses to CRH loading test. Postoperative responses of TSH and GH to TRH and GRH, respectively, were two fold higher than the preoperative levels. In contrast, basal and TRH-induced levels of serum PRL were decreased after surgery although both the basal and stimulated PRL levels were markedly high before surgery. In addition, gonadotropin response to GnRH examined in the same ovarian cycle was decreased in accordance with an increase in serum estradiol and progesterone levels after surgery. Improvement of hypercortisolemia even in a moderate case of Cushing's syndrome not only ameliorates hypertension, obesity and glucose intolerance, but also restores the accompanying dysfunctions of anterior pituitary, suggesting the clinical importance of early discovery and treatment of functioning adrenocortical incidentalomas.

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We report a 52-year-old woman who was noted to have elevated alkaline phosphatase (ALP), hypercalcemia (Ca: 11.7 mg/dL), and intact parathyroid hormone (intact PTH: 643.1 pg/mL), and then referred to our hospital with suspected hyperparathyroidism. Ultrasound examination of the neck and magnetic resonance imaging showed a mass region in the posterior aspect of the left lobe of the thyroid, and Tl-Tc subtraction scintigraphy showed Tl uptake at the same location. Based on laboratory and imaging studies, she was diagnosed with primary hyperparathyroidism. The excised parathyroid was a large mass measuring 6.8 × 2.8 × 1.9 cm in diameter and weighing 15.4 g. It was soft, covered with a thin capsule, did not infiltrate the thyroid parenchyma, and showed no evidence of malignant process. Histopathological examination showed that it was clear cell adenoma. There was no evidence of metastasis from the parathyroid tumor in other organs. The post-operative course was excellent, and serum PTH, Ca, and ALP levels returned to normal. Among parathyroid tumors, large adenomas are commonly considered to be more likely malignant, but in this case it was benign despite measuring more than 6 cm in diameter. The histopathological type of the adenoma was clear cell adenoma, a very rare type. We report a clear cell adenoma of the parathyroid gland, which has not been described previously in Japan.

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The development of silent thyroiditis in patients with a history of Graves' disease is common, especially in the postpartum period. We describe herein patients with Graves' disease who developed transient hyperthyroidism but not silent thyroiditis after withdrawal of antithyroid drug (ATD). If such patients are diagnosed as recurrence of Graves' disease, they may receive ATD or radioiodine therapy unnecessarily. We investigated the characteristics of these patients to prevent unnecessary therapy. We retrospectively studied 22 patients with Graves' disease who showed transient thyrotoxicosis after withdrawal of ATD. Two of 22 patients were male and the mean ages (± SD) were 33.7 ± 12.6 yr. We observed these patients for 28.5 ± 12.8 (mean ± SD; range 12–53) months after transient thyrotoxicosis, and measured TSH, FT4, and TSH binding inhibitor immunoglobulin in sera. Radioiodine uptake was measured in 6 of them. The radioiodine uptake in the 4 patients was not suppressed (27.5%, 28.0%, 32.7%, 38.1%). These uptake levels indicate that their thyrotoxicosis was not caused by silent thyroiditis. Most of the 22 patients became euthyroid within 6 months. This study suggests a new therapeutic option as follows: in the case of young patients with mild thyrotoxicosis after withdrawal of ATD, physicians should follow them up for one month without medication unless they have unbearable symptoms or complications.

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Limited clinical information is specified in the presentations, results of treatment and prognostic factors of follicular thyroid carcinoma with lung metastases. In order to better characterize the information, we retrospectively analyzed the data of 2,003 thyroid cancer patients who received treatment and follow-up at the Chang Gung Memorial Hospital during the period from January 1979 to December 2002. There were 1,516 cases of papillary and 272 cases of follicular thyroid carcinomas. In the study, lung metastases of the follicular thyroid carcinomas were defined as post-operative or follow-up chest X-ray, diagnostic or therapeutic ¹³¹I scan with positive finding of lung metastases. Serum thyroglobulin (Tg) levels under thyroxine treatment of patients with lung metastases had to be over 1.5 ng/mL. Of the follicular thyroid carcinomas, there were 70 (25.7%) with lung metastases including 50 females (mean age 54.1 ± 12.6 years old) and 20 males (mean age 59.4 ± 12.0 years old). Of the 70 patients, there were 53 patients (75.7%) who presented with lung metastases at the time of diagnosis. Of the 70 patients of follicular thyroid carcinoma with lung metastases, 30 patients (42.9%) died at the end of the follow-up, and only 4 patients improved to disease free status. The 5, 10, 15, and 20 year survival rates in these patients were 68.5%, 54.0%, 41.6%, 27.7%, respectively. Age, post-operative Tg level and tumor size are important prognostic factors which are demonstrated to be significantly different statistically between lung metastases group and the group of the patients without distant metastasis. Otherwise, only the tumor size and accumulative dose of ¹³¹I therapy demonstrate a significant difference between survival and mortality groups. Seventeen of the 70 patients developed lung metastases during the follow-up period. Mean period between diagnosis and recurrence of these patients was 3.6 ± 0.9 years. Over 75% of follicular thyroid carcinoma with lung metastases was diagnosed at the time of presentation. Forty percent (28/70 cases) of the follicular thyroid carcinoma with lung metastases had history of thyroid surgery in this study. If lung metastases are diagnosed in follicular thyroid carcinoma, it will be followed by a poor prognosis. Older patients, higher postoperative Tg, and larger tumor size in follicular thyroid carcinoma need aggressive postoperative treatment.

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To investigate the potential pathophysiologic role of human SRIF receptor gene expression in GH-secreting adenomas in acromegalic patients, we studied the relationship between the SRIF receptor gene expression, endogenous SRIF activity and exogenous response to octreotide in 16 acromagalic patients. Hypothalamic somatostatinergic activity (HSA) was assessed by glucose-induced suppression of TRH-stimulated TSH secretion. As an indicator of somatotrope sensitivity to HSA, glucose-induced suppression of TRH-stimulated GH secretion was determined. For the acute octreotide response, a 100 μg bolus of octreotide was injected intravenously and GH was measured hourly for 6 hr. Pituitary tumor SRIF receptor subtype 2 and 5 (sst2 and sst5) mRNA levels were measured by real-time RT-PCR. Gsp oncogene was also detected by direct PCR sequencing. Sst2 and sst5 mRNA levels were detected in all tumors. Sst2 mRNA levels positively correlated with that of sst5. Sst2 and sst5 mRNA levels did not show any correlation with basal GH values (nadir or peak). Expression of sst2, but not sst5, showed a positive correlation with the GH response to HSA, while the octreotide response positively correlated with the sum of sst2 and sst5 mRNA levels. Individuals with gsp-positive tumors were more responsive to octreotide than those with gsp-negative tumors but sst2 and sst5 mRNA levels did not differ between these two groups. These results suggest common transcriptional and/or post-transcriptonal regulatory mechanisms for these SRIF receptor subtypes within GH-secreting pituitary adenomas. The functional observations suggest that the degree (or level) of sst2 and sst5 expression is critical for the ultimate GH response of somatotropinomas to endogenous SRIF tone and exogenous SRIF analogue therapy. However, sst2 and sst5 mRNA levels are not the only factors mediating the response to SRIF.

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A case of malignant thymoma presenting as an anterior neck mass is reported. The tumor extended from the thyroid gland to the superior mediastinum. It did not accumulate Tc-99m pertechnetate, but continued to accumulate Tl-201 at the late phase. A fine-needle aspiration cytology from the tumor showed tight clusters of epithelial cells with crowded ovoid nuclei. The tumor was initially diagnosed as thyroid carcinoma, clinically and cytologically. A thymoma with a dominant epithelial component has to be considered in the differential diagnosis of a suspected papillary carcinoma of the thyroid.

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Primary aldosteronism is associated with glucose intolerance and diabetes, which is due in part to impaired insulin release caused by reduction of potassium, although other possibilities remain to be elucidated. To evaluate the in vivo effects of aldosterone on glucose metabolism, a single dose of aldosterone was administered to mice, which resulted in elevation of the blood glucose level. In primary cultured mouse hepatocytes, the gene expression of gluconeogenic enzymes such as glucose-6-phosphatase (G6Pase), fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase increased in response to aldosterone in a dose-dependent manner even at a concentration similar to a physiological condition (10^–9 M). The inhibitory effect of insulin on G6Pase gene expression was partially suppressed by aldosterone. Furthermore, aldosterone enhanced G6Pase promoter activity in human hepatoma cell line HepG2, which was prevented by co-treatment with a glucocorticoid antagonist RU-486, but not a mineralocorticoid antagonist spironolactone. In contrast, aldosterone had no effects on major insulin signaling pathways including insulin receptor substrate-1, protein kinase B, and forkhead transcription factor. These results suggest that aldosterone may affect the inhibitory effect of insulin on hepatic gluconeogenesis through the glucocorticoid receptor, which may be one of the causes of impaired glucose metabolism in primary aldosteronism.

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