Mechanical stress and parathyroid hormone (PTH) are major stimulators, and aging and glucocorticoids excess are important suppressors of osteoblast differentiation. Mechanical stress and PTH stimulate interleukin (IL)-11 expression in cells of osteoblast lineage by enhancing transcription of IL-11 gene via an increase in intracellular Ca²⁺. The elevated Ca²⁺ activates extracellular signal-regulated kinase (ERK) to enhance phosphorylation of cyclic AMP response element-binding protein (CREB), which binds to the fosB gene promoter and enhances ΔFosB expression. ΔFosB dimerizes with JunD on the IL-11 gene promoter to enhance its transcription. Both mechanical stress and PTH also stimulate phosphorylation of Smad1 via an activation of protein kinase Cδ (PKCδ). Phosphorylated Smad1 binds to the IL-11 gene promoter and forms complex with ΔFosB/JunD to further enhance IL-11 gene transcription. The increased IL-11 then suppresses expression of Wnt inhibitors, including Dickkopf 1 (Dkk1) and 2, and enhances Wnt signaling to stimulate osteoblast differentiation and inhibit adipocyte differentiation. The suppression of osteoblast differentiation by aging involves a decrease in IL-11 gene transcription by a reduction in JunD binding to the activator protein (AP)-1 site of the IL-11 gene promoter. Glucocorticoids inhibit transcriptional activation of IL-11 gene by an interaction of glucocorticoid-glucocorticoid receptor (GR) complex with ΔFosB/JunD heterodimer. Thus, factors that enhance osteoblast differentiation stimulate, and those which suppress osteoblast differentiation inhibit IL-11 gene transcription, and IL-11 enhances Wnt signaling by suppressing expression of its inhibitors. These observations are consistent with the notion that IL-11 mediates stimulatory and inhibitory signals of osteoblast differentiation by affecting Wnt signaling.

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Resveratrol (3,5,4’-trihydroxystilbene; RSV) is one kind of polyphenolic phytoalexin that has many effects on metabolic diseases. This study aimed to evaluate the protective effect of RSV pretreatment on β-cell. Male Sprague Dawley rats weighing 200-230 g were divided into 4 groups: (1) RSV; (2) streptozotocin (STZ, 70 mg/kg, intraperitoneally); (3) STZ after 7 days pretreatment with RSV; and (4) STZ pretreated with nicotinamide. Fasting glucose concentration was measured and an intraperitoneal glucose tolerance test was performed 72 h after STZ injection to determine the diabetic condition. The pancreas was removed 3, 6, 36, and 48 h after STZ injection. STZ induced diabetes in all rats not given RSV pretreatment, whereas none of the RSV-pretreated rats developed diabetes. Pretreatment with RSV inhibited apoptosis and reduced the activation of caspase-3 and poly(ADP-ribose) polymerase (PARP). However, expression of the total length PARP was not affected by pretreatment. Our findings suggest that RSV protects β-cells from STZ simultaneously with inhibiting the activation of PARP.

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McCune-Albright Syndrome (MAS) is a congenital endocrine disorder due to mosaic tissutal hyper-function. We describe a boy with a molecularly confirmed MAS, clinically evident with congenital café-au-lait spots, bone fibrous dysplasia, hyperthyroidism, and renal phosphate wasting syndrome. At 4.6 years of age he disclosed a rapid progression of peripheral puberty, so we decided to treat him with bicalutamide 25 mg/day and anastrozole 1 mg/day. Combined third generation aromatase inhibitors - competitive androgen receptor blockers were employed in familial male precocious puberty (FMPP). Combined treatment was performed for 49 months from the age of 4.6 to 6.7 years. The patient underwent clinical, laboratory, and instrumental evaluation twice a year from the first admission to the current age. This treatment caused a rapid normalization of growth velocity, subsequent reduction of penile androgenization, and stabilization of testicular volume. The therapy was well tolerated for all its duration and neither side effects, nor secondary hypothalamic activation were noted. This report provides further evidence of effectiveness and safety of combined third generation aromatase inhibitors - competitive androgen receptor blockers in male precocious peripheral puberty, firstly employed in male MAS, and contributes to expand the spectrum of disorders in which their employment may reveal promising.

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It is well-known that papillary thyroid carcinoma (PTC) has a generally indolent character and shows a favorable prognosis unless it has no high-risk features such as clinical lymph node metastasis, distant metastasis, and significant extrathyroid extension. In this study, we investigated the prognosis of 3,965 patients with PTC without these features. We classified these patients into 3 groups: T-1, tumor ≤ 2 cm (n = 2,591); T-2, tumor 2.1-4 cm (n = 1,123); T-3, tumor > 4 cm (n = 251). Ten-year recurrence rates of T-1, T-2, and T-3 patients were 0.3, 1.3, and 1.9% for the thyroid (in the subset of patients who underwent limited thyroidectomy), 1.9, 4.6, and 8.1% for lymph nodes, and 0.4, 1.6, and 3.4% for distant organs, respectively. A tumor size larger than 2 cm had an independent prognostic impact on all these recurrences also on multivariate analysis. These findings suggest that PTC larger than 2 cm exhibited more aggressive biological characteristics than that measuring 2 cm or less, even though it had no other high-risk features. However, the incidences of distant recurrence and carcinoma death were still low and it remains unclear whether extensive surgery is mandatory for otherwise low-risk PTC patients with large tumor.

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The relationship between insulin sensitivity (Si) and insulin secretion (β) was analyzed in 533 health examinees. The subjects underwent a 75 g oral glucose tolerance test, with plasma glucose (PG) and immunoreactive insulin (IRI) determined at fasting, 30 min and 120 min, and were classified according to the current criteria as normal glucose tolerance (NGT, n=328), non-diabetic hyperglycemia (NDH, n=113) including impaired fasting glucose and impaired glucose tolerance, and diabetes mellitus (DM, n=72). NGT was subdivided by fasting PG (FPG) tertile, ≤4.9, 5.0-5.4 and 5.5-6.0 mM, into NGT_FPG1, NGT_FPG2 and NGT_FPG3, or by body mass index (BMI) tertile, ≤21.8, 21.9-24.4 and ≥24.5 kg/m², into NGT_BMI1, NGT_BMI2 and NGT_BMI3. As an index of Si and β, Matsuda index=10,000/sqrt[FPG·FIRI·2hPG·2hIRI] and δIRI_0-30/δPG_0-30, were employed respectively: FIRI, 2hPG and 2hIRI denote fasting IRI, 2h-post glucose PG and IRI, respectively. Correlation between Si and β was evaluated by Spearman’s rank correlation and the parameters for [β]=a·[Si]^b were obtained by standardized major axis (SMA) regression. Si-β correlation was strongest in NDH (Spearman’s rho=-0.546, SMA regression r²=0.277), intermediate in DM (rho=-0.432, r²=0.193) and weakest in NGT (rho=-0.201, r²=0.039). Spearman’s rho for the Si-β correlation was significantly lower in NGT than in NDH (p=0.003). Si-β correlation was significant in NGT_FPG3, NGT_FPG2 and NGT_BMI3, but not in NGT_FPG1, NGT_BMI2 and NGT_BMI1. The slope, b, was -1.184˜-1.530 without significant differences between any groups. In conclusion, the hyperbolic Si-β correlation was weaker in NGT than in NDH and absent in NGT subjects belonging to the lowest FPG or BMI tertile.

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The relation between thyroid ultrasonography and laboratory, and the relationship of thyroid volume with clinical and anthropometric parameters, are not well clarified. Aim of the study was to investigate normal and hypoechoic-inhomogeneous not nodular thyroid gland in predicting thyroid tests, and to assess the correlation of thyroid volume with several clinical parameters. The series included 434 subjects (244 with normal thyroid ultrasonography, and 190 with hypoechoic-inhomogeneous thyroid) at their first evaluation. Subjects with normal ultrasonography and skewed tests were re-evaluated after one year. All subjects with normal ultrasound showed normal free-T₄, while TSH was elevated in 9.8% of cases and thyroid antibodies were positive in another 9.8%. In patients with hypoechoic-inhomogeneous thyroid, free-T₄ was low in 33.2%, TSH was elevated in 78.4% and thyroid antibodies were positive in 76.3%. Normal ultrasonography matched with normal tests in 81.1% of cases while hypoechoic-inhomogeneous thyroid in 9.5% (p<0.001). The re-evaluation of tests showed no significant difference. In subjects with both normal ultrasonography and tests, thyroid volume was correlated with age (p=0.001), weight (p=0.003), BMI (p=0.04), body surface area (p=0.002). Thyroid laboratory assessment was different between subjects with ultrasonographically normal or hypoechoic-inhomogeneous thyroid. Thyroid volume of thyroid diseases-free subjects was correlated with age, weight, BMI and body surface area, and this should be of interest to investigate the references of normality of thyroid size.

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Glycemic control is an important issue in gestational diabetes mellitus (GDM) and in diabetic pregnant women. We determined the reference intervals of glycated albumin (GA) and hemoglobin A1c (HbA1c) as glycemic control markers in healthy Japanese pregnant women and analyzed their time courses and factors that influence these variables during pregnancy. 676 women were screened for the present study. After the exclusion of non-pregnant and puerperal women, 574 women were studied to determine the reference intervals. HbA1c, GA, casual plasma glucose, urinary glucose, urinary protein, and body mass index (BMI) (non-pregnancy) were measured. HbA1c levels significantly decreased in the second trimester of pregnancy and increased in the third trimester, while GA levels significantly decreased towards the third trimester. Casual plasma glucose levels decreased in the first trimester and subsequently remained constant. The reference intervals of GA and HbA1c in the healthy pregnant women were 11.5-15.7% and 4.5-5.7%, respectively. GA levels were lower (p<0.01) and HbA1c levels were higher (p<0.05) in pregnant women with proteinuria. In the obese group, GA levels were lower (p<0.01) than those of the control group (18.5≤ BMI <25kg/m²), and HbA1c levels were higher (p<0.01) than those of the control group. On the basis of the results of this multicenter study, the reference intervals of GA and HbA1c in healthy Japanese pregnant women were determined. Strict glycemic control is essential to reduce perinatal complications. GA appears to be a useful marker for pregnant women, since it can be measured easily and changes rapidly and markedly.

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Patients with Turner syndrome (TS) almost develop osteoporosis, resulting from chromosomal deficiency and estrogen deficiency by gonadal dysgenesis. The aim of this study was to assess bone mineral density (BMD) during continuous estrogen therapy in young TS patients by measuring lumbar spine BMD of 67 TS patients using dual-energy X-ray absorptiometry. Twenty-seven patients who were treated with adult-doses of estrogen prior to the first evaluation, exhibited a significantly higher initial BMD than 30 patients treated with low-dose estrogen therapy and 10 patients without estrogen therapy (0.808 g/cm², 0.714 g/cm², and 0.664 g/cm², respectively). During continuous adult-dose estrogen therapy, BMD significantly increased in each group (maximum BMD during the study, 0.842 g/cm², 0.790 g/cm², and 0.724 g/cm², respectively). Initial and maximum BMD showed significant negative correlation with the age at which adult-dose estrogen therapy was initiated (r = -0.57 and -0.45, respectively). Among the patients not treated with adult-dose estrogen therapy prior to the first evaluation, the annual increase in the rate and amount of BMD was significantly higher when adult-dose estrogen therapy was initiated before age 18 (rate, 4.4 % before age 18 vs. 3.1 % after age 18; amount, 0.03 g/cm² before age 18 vs. 0.02 g/cm² after age 18). In summary, estrogen therapy increased BMD in young TS patients and might be more effective if initiated by age 18.

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Kisspeptin/metastin has been implicated as a critical regulator in luteinizing hormone (LH) secretion and the reproductive system mediating the effect of estrogen on GnRH neurons. In the present study we examined the sex differences in the effects of estrogen on Kiss1/kisspeptin expression in the forebrain by using gonadectomized rats to assess the interaction of kisspeptin and GnRH neurons. Kiss1/kisspeptin cell bodies were abundant in the rostral periventricular area of the third ventricle (RV3P) and the arcuate nucleus (ARC). A few cell bodies were also observed in other portions of the forebrain, i.e. the bed nucleus of the stria terminalis (BST), the paraventricular hypothalamic nucleus (PaAP), the ventromedial hypothalamic nucleus (VMH), and the medial amygdaloid nucleus (MeA). Kisspeptin-immunoreactive fibers were found mainly in the median eminence (ME), the ARC, and the RV3P, but were scarce in the preoptic area (POA), where GnRH neurons are localized. We also found that estrogen triggers expression of the Kiss1 gene and peptide within all the regions except the ARC, and that the effects in the RV3P, BST, PaAP, and VMH are greater in estrogen treated ovariectomized female rat. It is noteworthy that kisspeptin and GnRH neurons were densely associated in the ME but were rarely in contact in the POA. Thus, our results suggest that kisspeptin-positive neurons, except for the ones in the ARC, are related not only to estrogen-positive feedback, but also sex dimorphism, and that kisspeptin regulates GnRH release in the ME rather than the POA.

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Measurement of 24-hour radioactive iodine uptake (RAIU), which is commonly used to calculate the dose of radioiodine (RI) therapy, cannot be accomplished in a single day. The purpose of this study was to predict 24-hour RAIU from 3-hour RAIU in Japanese patients with Graves’ disease, and to investigate other factors that could be used to predict 24-hour RAIU. A total of 66 Japanese patients (14 men and 52 women; age, 17-83 years) with Graves’ disease who had undergone both 3-hour and 24-hour ¹²³I RAIU measurements between January 2006 and September 2011 were included in this study. Stepwise multiple regression analyses were performed in order to identify factors that could be used to predict 24-hour RAIU. The investigated factors were gender, age, thyroid volume, TSH, free thyroxine (FT4), free triiodothyronine (FT3), serum creatinine, second generation assay TSH receptor antibody (TRAb2), antithyroid drugs discontinuation period (ADP), iodine restriction period and 3-hour RAIU. The ADP was converted to an ordinal scale ADP score (ADPS) for multiple regression analyses. Multiple regression analyses showed that 3-hour RAIU (P < 0.001), FT3 (P < 0.001) and ADPS (P < 0.001) were statistically significant predictive factors of 24-hour RAIU. The relationship between 24-hour RAIU (LU) and 3-hour RAIU (EU), FT3 and ADPS was: LU = 11.5 + 29.1 × log₁₀ EU + 23.0 × log₁₀ FT3 - 2.7 × ADPS (r = 0.82, P < 0.001). The present results indicate that prediction of LU from EU, FT3 and ADPS is feasible in Japanese patients with Graves’ disease.

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