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An adequate maternal iodine intake during pregnancy and lactation is essential for growth and mental development in fetuses and newborns. Both deficient and excess iodine may disrupt normal thyroid function. There are limited data on perinatal iodine metabolism in mothers and infants, as well as the effect of povidone-iodine (PVP–I) antiseptics used in Cesarean delivery. The urinary iodine concentration (UIC), serum iodine, thyrotropin (TSH), free thyroxine (FT4) and breast milk iodine concentration (BMIC) were measured consecutively in a total of 327 mothers and 249 term-infants in two prospective studies. The maternal median UIC was 164 µg/L in the third trimester, increased to 256 µg/L on postpartum day 2, then decreased to 116 µg/L one month later. The BMIC on postpartum days 2 and 30 was 17.6 and 13.5 µg/100g, respectively. In neonatal infants born to the mothers unexposed to PVP-I, the median UIC was 131 µg/L in the first voiding urine and increased to 272 µg/L on day 4, then slightly decreased to 265 µg/L on day 28 suggesting sufficient iodine reserve at birth. PVP-I antiseptics containing 1g of iodine for skin preparation at Cesarean delivery transiently increase maternal serum iodine concentration, UIC and BMIC, however, it has little effect on maternal TSH, FT4 and neonatal UIC, TSH, or FT4. The iodine status of pregnant women and their infants was adequate in this population; however, the UIC in lactating mothers at one postnatal month was low enough to suggest iodine deficiency or near iodine deficiency. Further studies are necessary. This study was not registered to any clinical trials registry (CTR).

Thyroid diseases in pregnant and lactating women may result in adverse outcomes for both mothers and infants. A reference range for thyroid function is required in different areas; however, few studies on the gestational change or reference ranges of thyrotropin (TSH) and free thyroxine (FT4) concentrations for Japanese pregnant women have been reported. To establish the gestational trimester-specific reference ranges of serum TSH and FT4 concentrations, our previously published data on 481 pregnant women with the mean age of 30.8 years who provided serum samples as early as gestational week (GW) 6 was compiled by using their percentile values. The overall median urinary iodine concentration (UIC) during pregnancy was 201 μg/L suggesting adequate iodine intake. The prevalence of positive serum thyroid autoantibody (ThAb), i.e., antithyroid peroxidase antibody (TPOAb) and antithyroglobulin antibody (TgAb), was 11.4%. The reference ranges (2.5-97.5th percentile) of serum TSH and FT4 concentration calculated for samples with negative TgAb and TPOAb were 0.04-6.06 mIU/L in the first trimester (T1), 0.31-3.11 mIU/L in the second trimester (T2) and 0.48-3.93 mIU/L in the third trimester (T3) for TSH, and 1.10-1.87 ng/dL (T1), 0.76-1.56 ng/dL (T2) and 0.76-1.14 ng/dL (T3) for FT4. Compared to published data around the world in the 2017 American Thyroid Association (ATA) guideline, both the upper and lower limits of our TSH and FT4 reference ranges in the first trimester were higher than those in other countries. Further research is necessary in larger samples.

Context Japan has been regarded as a long-standing iodine-sufficient country without iodine fortification; however, data on nationwide iodine status are lacking. Objective This study aimed to characterize the iodine status in Japan. Methods From 2014 through 2019, a nationwide school-based survey was conducted across all districts in Japan. Urinary iodine concentration (UIC), creatinine (Cr) concentration, and anthropometry were assessed in healthy school-aged children (SAC) aged 6 to 12 years. Their iodine status is regarded as generally representative of the nation’s iodine status. Results A total of 32 025 children participated. The overall median UIC was 269 μg/L, which was within the World Health Organization’s adequacy range. There was a regional difference in UIC values within 14 regions, and the lowest and highest median UICs were found in Tanegashima Island (209 μg/L) and Nakashibetsu, Hokkaido (1071 μg/L), respectively. The median UIC ≥ 300 μg/L was observed in 12 of 46 regions. By using estimated 24-hour urinary iodine excretion (UIE), the prevalence of SAC exceeding the upper tolerable limit of iodine for Japanese children was from 5.2% to 13.7%. The UIC values did not change with age, body surface area and body mass index percentile, whereas the Cr concentration simultaneously increased suggesting the effect of urinary creatinine on UI/Cr and estimated 24-hour UIE values. Conclusions The iodine intake of Japanese people is adequate, but in some areas it is excessive. The incidence and prevalence of thyroid disorders associated with iodine intake should be obtained, especially in the areas where high amounts of iodine are consumed.

Selenium (Se), molybdenum (Mo), and iodine (I) are essential trace elements or nutrients and their adequate intake is essential for human health. These elements in foods are easily absorbed from the digestive tract and excreted predominantly into the urine, and their nutritional status is reflected in urinary excretion; however, information on the variability of urinary excretion is limited. To characterize the urinary Se, Mo, and I concentrations and their intra- and inter-individual coefficients of variation (CV), correlation, and seasonal change, spot urine samples were collected from 24 healthy university students, 10 males and 14 females, with the mean age of 20.6 years, for 10 consecutive days in each of the four seasons according to a defined schedule of an interval of 3 months throughout 1 year. The median Se, Mo, and I concentrations for all urine samples (n = 947) were 52.8, 127.0, and 223 μg/L, respectively. The Se and Mo intakes were highest in summer and lowest in spring, while the I intake was highest in autumn and lowest in summer. In all three elements, the intra-individual CVs were smaller than their inter-individual CVs. The log-transformed intra- and inter-individual CVs were 10.5 and 14.7% for Se, 12.3 and 15.1% for Mo, and 15.5 and 18.1% for I. There was no gender difference in Se and I concentrations, while Mo and Mo/Cr values in males were higher than those in females. Our results suggest adequate nutritional status of Se, Mo, and I with a relatively smaller variability of dietary intake except for I in this population.

The daily consumption of iodine in Japan is higher than in most countries, and there are few reports on iodine metabolism and variance of habitual iodine ingestion in an iodine-sufficient area. To elucidate the patterns of short-term urinary iodine excretion (UIE) and long-term variability of habitual iodine intake, the urinary iodine excretion process after a high dietary iodine load of 3 mg was observed in eight Japanese adults under strict supervision with complete urine collections for three days. In addition, estimated UIE and dietary iodine intake (DII) were assessed in 24 university students using repeated spot urine samples of ten consecutive days and a food frequency questionnaire in each of the four seasons. Approximately 50, 75 and 90% of orally ingested iodine was excreted into the urine at 8, 13 and 22 hours after ingestion, respectively. Almost an equal amount of ingested iodine in meals was cleared within 33.5 h after eating with a maximum excretion rate at 3-4 h. There was a high fluctuation in the UIE and DII in the university students. The intra- and inter-individual crude coefficients of variation were 123 or 294.7% for UIE, and 58.3 or 88.7% for DII, respectively, indicating a higher variance of habitual iodine intake than in other countries. The frequency of occurrence for UIE above 3 mg was every 43 days. Rapid renal clearance of iodine and high variability as well as low frequency of dietary iodine intake might prevent people from being exposed to an excess iodine intake over the long term in Japan.

Iodine is an essential component of thyroid hormones and a dietary micronutrient for humans, and adequate iodine intake is necessary to maintain thyroid function. A population's iodine intake and nutritional status are assessed based on urinary iodine excretion. There are few studies on iodine nutritional status for all age groups residing in the same area in Japan. Between 2010 and 2017, a total of 769 healthy subjects aged 6.4-73 years in three sites in Yokohama City, were enrolled in the survey. The urinary iodine concentration (UIC), iodine to creatinine (Cr) ratio (UI/Cr) and estimated 24-h urinary iodine excretion (UIE) in single spot urine samples were measured, and habitual dietary iodine intake was assessed by food frequency questionnaires. The estimated 24-h UIE was calculated using individual predicted 24-h creatinine excretion by the validated equations developed for healthy Japanese children and adults which vary by age, gender and anthropometry. The median UIC for all participants was 219 μg/L, suggesting adequate iodine intake for this population. There was an increasing trend in median UI/Cr and estimated 24-h UIE by age. A significant correlation between UIC and UI/Cr (r = 0.6378), UIC and estimated 24-h UIE (r = 0.6804), and UI/Cr and estimated 24-h UIE (r = 0.5756) were observed. These estimates can be feasible, convenient and alternative methods to 24-h urine collection in order to assess iodine status in some populations such as ethnically or racially homogeneous and well-nourished people. Additional studies are required to validate these findings.

Iodine is an essential nutrient for thyroid hormone synthesis, and iodine deficiency especially in pregnant and lactating women results in serious damage to their infants. To characterize iodine nutrition throughout gestation by using a food frequency questionnaire (FFQ) and urinary iodine concentration (UIC) measurement, and to establish appropriate gestational age-specific reference ranges for serum TSH and FT₄ in thyroid autoantibody (ThAb) negative euthyroid Japanese women, a total number of 563 pregnant women including 422 subjects with negative ThAbs, 105 postpartum women and their 297 newborn infants were included in the study. Dietary iodine intake (DII) was evaluated by FFQ. Serum TSH, FT₄ and UIC were sequentially determined in the three trimesters of pregnancy and at the 31st postpartum day. The overall median UICs throughout pregnancy and in the postpartum period were 224.0 and 135.0 μg/L, respectively, suggesting sufficient iodine nutrition. The median DII was 842.4 μg/day in pregnant women. The median UIC in the first trimester (215.9 μg/L) significantly decreased in the second trimester (136.0 μg/L). The prevalence of pregnant women with a UIC below 150 μg/L was 31.6% and that in lactating women with a UIC below 100 μg/L was 33.3%. The pattern of gestational change in serum TSH and FT₄ was comparable to that in iodine-sufficient areas. A substantial percentage of women might be at risk for iodine deficiency if there is a restriction of iodine-rich foods. However, iodine supplementation for pregnant women must be carefully balanced against the risk of iodine excess particularly in Japan. Further research in larger samples is needed.

Proteoglycans synthesized by osteoblasts are incorporated into bone matrix and thought to play a role in bone metabolism. Transforming growth factor (TGF) beta affects the synthesis of matrix proteins, including proteoglycans, in various stromal cells, and proteoglycans, especially decorin, are associated with matrix collagen. In the present study, the effects of TGF-beta 1 and L-ascorbate, a factor essential for collagen synthesis, on the synthesis and distribution of proteoglycans were examined using murine osteoblast-like MC3T3-E1 cells. TGF-beta 1 stimulated the synthesis of proteoglycans in MC3T3-E1 cells. Among various proteoglycans, the synthesis of decorin was preferentially enhanced by TGF-beta 1, and the effect was more pronounced on secreted decorin compared to that associated with the cell/matrix layer. TGF-beta 1 also stimulated the initiation and elongation of the dermatan sulfate glycosaminoglycan chain, resulting in a larger molecular size of decorin. TGF-beta 1 influenced the synthesis of a heparan sulfate proteoglycan only slightly. L-ascorbate had no effect on the synthesis of proteoglycans, but increased those associated with the cell/matrix layer. Furthermore, when L-ascorbate was added to the culture along with TGF-beta 1, the percentage of proteoglycans associated with the cell/matrix layer increased from 25.8 +/- 1.0 to 41.0 +/- 0.5%. These data demonstrate that TGF-beta 1 markedly stimulates the synthesis of proteoglycans, especially decorin, mainly as a secreting form, that the accumulation of decorin into matrix is enhanced by L-ascorbate, and that the effects of TGF-beta 1 and L-ascorbate are additive.(ABSTRACT TRUNCATED AT 250 WORDS)

Glycogen storage disease type 1a (GSD 1a) is an autosomal recessive metabolic disorder caused by a deficiency in glucose-6-phosphatase (G6Pase). We analyzed the G6Pase gene of two unrelated Japanese families with GSD 1a. DNA sequencing of all five exons and exon-intron junctions revealed a G-to-T transversion at nucleotide 727 (G727T) in exon 5, which has been previously reported to cause abnormal splicing. Family studies using mismatch PCR showed that three patients were homozygous for the G727T mutation, while the parents were heterozygous. To investigate allele frequencies, we screened 216 Japanese healthy volunteers and found one asymptomatic carrier. Our findings suggest that the G727T mutation may be prevalent in Japan.

We examined 2,046 adults (834 males and 1,212 females aged 20-75 years) from polluted district in East Slovakia (POLL) and two neighboring upstream and upwind located districts of background pollution (BCGR). By ultrasound we estimated the thyroid volume (ThV), hypoechogenicity (HYE), nodules and cysts. Serum levels of thyrotropin (TSH), thyroperoxidase antibodies (TPOab) and thyroglobulin were estimated by electrochemiluminiscent assay and these of 15 PCB congeners, p,p'-DDE, p,p'-DDT, hexachlorobenzene (HCB) and hexachlorocyclohexane by high-resolution gas chromatography. In 320 subjects also selected hydroxylated and methylsulfonated PCB metabolites, polychlorinated dibenzo-dioxins (PCDDs), -furans (PCDFs), five dioxin-like coplanar and eight mono-ortho PCB congeners were estimated. Urinary iodine was measured by automatic microplate method. Reciprocal positive association was found between three major POPs (PCBs, DDE and HCB), the levels of these and also PCDDs plus PCDFs in polluted area being considerably higher than in background pollution area. ThV in groups of males and females from POLL with high PCBs level was significantly higher (p0.001 by t-test) then in age and sex matched groups from BCGR with low PCBs level. In 1,048 males and females aged60 years with serum PCBs level1,000 ng g(-1) lipid (median=1,756 ng g(-1)) a significant effect of age on ThV was found (p0.01 by ANOVA), while in 921 respective subjects with PCBs level1,000 ng g(-1) (median=661 ng g(-1)) it was not. These findings supported the view on the additional effect of PCBs on ThV other than that of age. Since the urinary iodine in both districts showed optimal range, any interfering effect of unsatisfactory iodine intake on ThV may be excluded. The frequency of autoimmune thyroiditis signs such as HYE, increased serum level of TPOab and TSH resulting in subclinical or overt thyroid hypofunction was positively associated with sex, age and organochlorine levels. The increase of such frequency in males with POPs levels was much more abrupt than that in females. No considerable differences in the frequency of thyroid nodules as related to PCBs level were found.

In a certain area of Michalovce district in East Slovakia, heavy industrial pollution by polychlorinated biphenyls (PCBs) developed in 1955-1984 and very high PCB levels in environmental and human samples are still persisting. Recently, a total of 2045 adults from this and the surrounding background pollution area have been examined using questionnaire data, thyroid volume by ultrasound (ThV), urinary iodine and serum levels of 15 PCB congeners, hexachlorobenzene (HCB), 2,2'-2-bis(4-chlorobiphenyl)-1,1-dichloroethylene (DDE), 2,2'-bis(4-chlorophenyl)-1,1,1-trichloroethane (DDT), alpha-, beta- and gamma-hexachlorocyclohexane (HCH), thyrotropin (TSH), free thyroxine (FT4), anti-thyroperoxidase antibodies (TPOab) and fasting glucose. As based on our previous findings of strikingly high level of PCBs in fish from high pollution area (e.g. mean level of 375430 ng/g lipid) and considerably lower, but still relatively high level in background pollution area (e.g. mean PCB level of 5150 ng/g), the information on the frequency of fish meals and approximate annual consumption of fish from local waters was obtained by questionnaires. The association of contaminated fish consumption with very high blood levels of PCBs, DDE and HCB and increased ThV as well as with increased frequency of positive TPOab, high values of FT4 and impaired fasting glucose (IFG) was found. These associations were also confirmed in 16 marital pairs from high pollution area with very high PCB level in both members associated with high fish consumption. It was concluded that, due to persistent heavy pollution of waters, soil and food chain namely by PCBs, but also by pesticides (e.g. DDE and HCB) resulting from their previous extensive use in agriculture, the fish from local waters still remains the most important source of these toxic pollutants which results in considerable adverse health effects.

Iodine deficiency disorders (IDDs) are serious global public health problems and approximately 2 billion people are at risk of IDD complications. Urine iodine and thyroid size by ultrasound in school-age children are important indicators for assessing IDD in a population. Interpretation of sonographically measured thyroid volume requires valid reference criteria from iodine-sufficient populations, and in 2003 WHO (World Health Organization)/ICCIDD (International Council for the Control of Iodine Deficiency Disorders) proposed new international reference values for thyroid volume in children aged 6-12 years. To establish a normative reference of thyroid volume and characterize the current status of iodine nutrition in Japanese schoolchildren in Tokyo, where iodine deficiency has never existed, a total of 654 subjects aged 6-12 years (317 girls and 337 boys) in three primary schools were enrolled in the study in 2002. Thyroid volume was determined by using the standardized method recommended by WHO/ICCIDD and the iodine concentration in spot urine samples and the anthropometric measurements were evaluated. Thyroid volume was positively correlated with the children's age, height, weight, or BSA. Regardless of gender the computed median and 97th percentile thyroid volumes based on age or BSA in Japanese children were generally lower than the corresponding values recently reported in iodine-sufficient areas, although these values were slightly higher (5-13%) than those in the 2003 WHO/ICCIDD international reference. The computed median value of urinary iodine concentration was 281.6 microg/L (303.7 microg/gCre) and extremely high values exceeding 1,000 microg/L were found in 16% of the subjects. The present study clearly indicated a high iodine intake in Japanese schoolchildren and also established reference values for thyroid volume that might be applicable to countries in the Far East as a population-specific local reference.

BACKGROUND: There is increasing concern about endocrine-disrupting chemicals (EDCs) which may produce adverse health effects in humans and other species. One such chemical, bisphenol-A (BPA), a monomer of polycarbonate plastics, is widely used in consumer products; it has been reported to contain estrogenic activity through binding to estrogen receptors. Cytochrome P450 mono-oxygenase 3A4 (CYP3A4) is one of the key enzymes for the metabolism of endogenous steroids and foreign chemicals in liver. The orphan nuclear receptor, steroid and xenobiotic receptor (SXR/PXR), has recently been isolated. A variety of known inducers of CYP3A4 bind to SXR/PXR, and stimulate transcription on xenobiotic-response elements (XREs) located in the promoter region of the CYP3A4 gene. Recent study has shown that EDCs, diethylhexylphthalate (DEHP) and nonylphenol, but not BPA, induce mouse SXR/PXR-mediated transcription. However, it is known that species differences in SXR alter CYP3A inducibility. OBJECTIVE: To test whether BPA stimulates human SXR/PXR-mediated transcription using reporter gene assays. METHODS: Transfection assays were performed with human SXR/PXR expression plasmid and a reporter plasmid containing the XREs in the CYP3A4 gene promoter in HepG2 cells. BPA-induced interaction of human SXR/PXR with steroid receptor coactivator-1 (SRC-1) was analyzed by mammalian two-hybrid assays. RESULTS: BPA, as well as DEHP, activated human SXR-mediated transcription on the XREs. In mammalian two-hybrid assays, BPA recruited SRC-1 to the ligand-binding domain of human SXR/PXR. CONCLUSIONS: Our observations have indicated that BPA may be a human-specific inducer of the CYP3A4 gene, and may influence the metabolism of endogenous steroids, drugs, and other xenobiotics.

Objective We investigated preoperative and postoperative serum alpha-subunit levels and the alpha-subunit response to TRH in patients with various types of pituitary tumour and correlated the data with histological findings in order to clarify the significance of alpha-subunit measurement in pituitary adenomas. Patients We examined 59 patients with pituitary tumours (22 with GH cell adenomas, 30 with clinically nonfunctioning adenomas and seven with other tumours) treated at Toranomon Hospital between 1996 and 1998. Results The basal alpha-subunit level was supranormal in six out of 22 (27%) patients with a GH cell adenoma and in nine out of 30 (30%) patients with a nonfunctioning adenoma. A paradoxical alpha-subunit response to TRH was found in seven out of 22 (32%) patients with a GH cell adenoma. These seven patients also showed a paradoxical GH response to TRH administration. In addition, paradoxical response to TRH was found in eight out of 30 (27%) patients with a clinically nonfunctioning adenoma. In contrast, patients with other types of pituitary tumour showed neither a supranormal alpha-subunit level nor a paradoxical response to TRH. The supranormal alpha-subunit level and the abnormal response to TRH were normalized in both GH cell adenoma and nonfunctioning adenoma patients after successful surgery. Immunohistochemical studies showed alpha-subunit positive cells in 51% of GH cell adenomas or nonfunctioning adenomas and there was a good concordance with the serum alpha-subunit levels in both GH cell adenoma and nonfunctioning adenoma patients. Conclusions These findings suggest that supranormal serum alpha-subunit levels are mainly due to hypersecretion by the tumour itself, while the paradoxical alpha-subunit response to TRH is an associated phenomenon in patients with a GH cell adenoma or nonfunctioning adenoma. The alpha-subunit level and the response to TRH may be useful indicators for assessing the operative outcome, especially in nonfunctioning adenoma patients who have no other definite endocrine markers.

Myocilin is known to be associated with the pathogenesis of juvenile-onset primary open angle glaucoma. The tissue distribution of myocilin transcripts has been analyzed in both humans and mice, and a high level of expression in the retina and skeletal muscle has been reported. The functions of myocilin in these tissues are unknown. We isolated rat myocilin cDNA and examined the expression pattern of myocilin, including its expression in endocrine organs, using Northern blot analysis. The rat myocilin cDNA sequence has two in-frame initiation codons, the upstream and downstream ATGs corresponding to the initiation codon of human and murine myocilin, respectively. It is most likely that the first ATG is a translational initiation codon, since 8 of 13 amino acid residues deduced from the rat cDNA sequence between the first and the second ATGs are the same as those in human myocilin. The open reading frame encodes 502 amino acids. Rat myocilin also has both a myosin-like domain and an olfactmedin-like domain, which have been identified in human and murine myocilin. Northern analysis of rat myocilin mRNA revealed substantial expression in the thyroid gland, as well as in the retina and muscle. No transcripts were detected in other endocrine glands, including the adrenal gland, pituitary, and testis. Myocilin may play an important role in thyroid function. Further study of the expression and role of myocilin in the thyroid is required.

To clarify the clinical significance of elevation of serum aminotransferase levels in anorexia nervosa, we analyzed the relationships of serum aminotransferase levels to other serum biochemistry and physical conditions before and during refeeding therapy in 101 patients with anorexia nervosa. Before refeeding therapy, body mass index (BMI) was distributed from 9.9 to 16.4 kg/m2 (13.2 ± 1.3, mean ± SD), and 29 patients (28.7 %) showed abnormally high aminotransferase levels. Among 17 patients with a BMI of less than 12 kg/m2, the aminotransferase level was abnormally high in 13 patients (76 %). Incidence and severity of serum aminotransferase elevation were greater in the patients with lower BMI. The groups with high serum aminotransferase levels had a lower body temperature, lower pulse rate, and higher incidence of other biochemical abnormalities than the group with normal serum aminotransferase levels. These findings indicate that aminotransferase elevation develops at a high incidence in anorectic patients with a critically life-threatening condition, and it is a sign of multiorgan failure requiring urgent calorie repletion. This type of aminotransferase elevation is to be distinguished from refeeding-induced aminotransferase elevation.(Internal Medicine 37: 32-39, 1998)

甲状腺疾患の診断・治療はホルモンや抗体の微量測定が進歩したおかげで,大変楽になった様に見える.しかし,患者を前にして,問診,触診,考えながら検査を選ぶ重要性は昔も今も変わらない.このような意味で,問診の段階から検査の選択まで,出来る限り現場の実際に即した形で,診断の要点を記載したつもりである.甲状腺ホルモンの組織における作用に良いindicatorのない現状では,症候や理学所見からのスケーリングが大切なことも理解していただきたいと思う.

A series of 44 patients with acromegaly underwent transsphenoidal surgery between 1987 and 1996. The early postoperative mean basal GH level

Objective Previous studies of Pit-1 expression in human pituitary tumours have produced conflicting results. We have studied expression of Pit-1 mRNA in human pituitary adenomas, as well as in normal human and rat pituitaries, and results were compared with clinical, histological, and immunohistochemical features. In addition, expression of GH, PRL, and TSH-beta mRNA was also studied and compared with Pit-1 gene expression. Material and methods The adenomas consisted of 13 GH cell adenomas, 7 PRL cell adenomas, 3 TSH cell adenomas, 4 ACTH cell adenomas, and 10 clinically non-functioning adenomas. Expression of the Pit-1, its isoforms, and each hormone, was studied using the reverse transcription polymerase chain reaction. Results Pit-1 mRNA was expressed not only in normal human and rat pituitaries, but also in all GH, PRL and TSH cell adenomas. There was no correlation between Pit-1 transcripts and biological behaviour or histological findings in these three types of adenoma, suggesting that Pit-1 is generally required for the determination of cell phenotype but is insufficient for the regulation of hormonal activity and tumour growth in these pituitary adenomas. In addition, Pit-1 was also expressed in some ACTH cell (2/4) and non-functioning adenomas (7/10). Although there were no GH, PRL or TSH-beta transcripts in Pit-1 mRNA-negative ACTH cell and non-functioning adenomas, PRL mRNA was detected in all Pit-1 mRNA-positive ACTH cell adenomas and GH, PRL and/or TSH-beta mRNA were found in four of seven Pit-1 mRNA-positive non-functioning adenomas. In contrast, Pit-1 mRNA was expressed without any GH, PRL, or TSH-beta transcripts in only three non-functioning adenomas. These data suggest that expression of Pit-1 mRNA in these two types of adenomas can be mainly attributed to the presence of GH, PRL and/or TSH-beta mRNA expressing cells and that true Pit-1 transcripts found in non-functioning adenomas may be a rare event. Moreover, there were two cases which expressed Pit-1 alpha mRNA, but failed to show other Pit-1 isoform mRNA. There were, however, no clinical or histological differences between these two adenomas showing only Pit-1 alpha mRNA and the others expressing both Pit-1 alpha mRNA and other Pit-1 isoform mRNA. Conclusions Pit-1 mRNA was expressed not only in GH, PRL and TSH cell adenomas but also in other types of adenoma. However, it is suggested that expression of Pit-1 mRNA in most ACTH cell and non-functioning adenomas can be attributed to GH, PRL and/or TSH-beta mRNA expressing cells. Further studies are necessary to elucidate the role of Pit-1 transcripts in the three non-functioning adenomas without GH, PRL and/or TSH-beta mRNA expression.

To investigate whether adenohypophysial hormone expression is heterogeneous within individual clinically nonfunctioning pituitary adenomas, immunohistochemical examinations were performed on tissues obtained by multiple sampling of 11 adenomas. Stained sections were assessed by morphometric image analysis as well as semiquantitative estimation under microscopy. All tumors except one were immunopositive for one or more gonadotropins. Results were divided into five grades based on the proportion of immunoreactive cells per section. Semiquantitative estimation showed only a one-grade difference among samples from the same tumor in four cases for FSHB and in two cases for LHB. These qualitative similarities between multiple samples were confirmed by morphometric image analysis. From the practical standpoint of making a diagnosis of nonfunctioning pituitary adenoma, it is not necessary to take into account immunohistochemical heterogeneity within an individual tumor, and immunohistochemical findings in a given sample obtained at surgery can be regarded as representative of the entire adenoma.

Imai Y, Ibaraki K, Odajima R, Shishiba Y. Analysis of proteoglycan synthesis by retro-ocular tissue fibroblasts under the influence of interleukin 1β and transforming growth factor-β Eur J Endocrinol 1994;131:630–8. ISSN 0804–4643 Retro-ocular tissue fibroblasts are supposed to be responsible for the deposition of glycosaminoglycan in Graves' ophthalmopathy. We have reported in a preliminary fashion that interleukin 1β (IL-1β) and transforming growth factor-β (TGF-β) increased the rate of [35S]sulfate incorporation into proteoglycans two to five times the control in culture of retro-ocular tissue fibroblasts. The increase in the rate of [ S]sulfate incorporation into proteoglycan will occur as a result of: (a) net increase of proteoglycan synthesis; (b) elongation of glycosaminoglycan chains; (c) increased number of glycosaminoglycan chains; (d) oversulfation of glycosaminoglycan chains; (e) increase in cell number; (f) decreased rate of degradation. We have analyzed which mechanism is important for the increase of [35S]sulfate into proteoglycans observed in human retro-ocular tissue fibroblasts under the influence of cytokines. The last two possibilities (e, f) were ruled out because during the observation period there was no consistent proliferation of the cells and no decrease in the rate of degradation of proteoglycan examined by pulse-chase experiment. Cytokines did not change the size of glycosaminoglycan chains released from proteoglycan as measured by alkaline borohydride treatment, ruling out (b). Disaccharide analysis by HPLC after chondroitin sulfate ABC digestion revealed that glycosaminoglycan mainly contains monosulfated chondroitin disaccharides and that oversulfation was not observed under the influence of IL-1β or TGF-β, ruling out (d). The capacity to synthesize glycosaminoglycan chain in the presence of an artifical acceptor of chain elongation, β-d-xylodide, was increased significantly by IL-1β but not obviously so by TGF-β. Thus, an increased number of glycosaminoglycan chains (c) is possible for IL-1β. A preliminary northern blot analysis employing probes for mRNAs for various proteoglycan core proteins showed increased expression of versican and aggrecan in the presence of IL-1β or TGF-β. This result supports the possibility of (a). In conclusion, IL-1β and TGF-β increased [35S]sulfate incorporation into proteoglycan by increasing the net increase of proteoglycan synthesis and possibly by increasing the number of glycosaminoglycan chains attached to core protein in the case of IL-1β. Y Shishiba, Division of Endocrinology, Department of Medicine, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo, Japan

A 62-year-old woman had primary hyperparathyroidism due to parathyroid carcinoma. In spite of surgical removal of the enlarged parathyroid gland, intractable hypercalcemia persisted. 99mTc-methoxyisobutylisonitrile scanning revealed bone metastatic lesions, although conventional 201Tl-chloride scanning failed to demonstrate those lesions. Octreotide inhibited parathyroid hormone (PTH) secretion, although various means such as bisphosphonates, calcitonin and hydration were effective to reduce serum calcium level to some extent but failed to reduce PTH secretion at all. The CT-guided transcutaneous tumor marking facilitated the subsequent orthopedic surgery for successful removal of the metastatic focus of PTH secretion from the iliac bone.(Internal Medicine 33: 697-702, 1994)

Iodine deficiency in pregnant and lactating women results in serious damage to their fetuses, newborns, and weaning infants. The effect of dietary iodine intake on maternal and infantile thyroid function has not been well studied in iodine-sufficient areas, and there are few data on appropriate gestational age-specific reference ranges for urinary iodine excretion during pregnancy and lactation.The aim of the study was to characterize the gestational change of urinary iodine excretion in Japanese women and to assess the effects of iodine status on thyroid function in mother and infant.A total of 934 Japanese women and their 722 newborn infants were enrolled in the study. Iodine and creatinine concentrations were determined in spot urine samples in the three trimesters of pregnancy and the postpartum period at 34.0 d after delivery. Serum thyroperoxidase antibody and thyroglobulin antibody, TSH, and free T(4) were measured in each trimester, and neonatal TSH was measured on postnatal d 4.The overall median urinary iodine concentration (UIC) during pregnancy was 219.0 μg/liter, higher than that in postpartum women (135.0 μg/liter). The prevalence of pregnant women with low UIC less than 100 μg/liter or high UIC greater than 500 μg/liter was 16.1 and 22.2%, respectively. Urinary iodine excretion decreased from 221.0 μg/liter in the first trimester to 208.0 μg/liter in the second trimester to 193.0 μg/liter in the third trimester, and then remained at 135.0 μg/liter postpartum. [corrected]. The maternal UIC correlated positively with serum TSH during pregnancy. There was no significant difference in UIC between subjects with positive thyroid autoantibodies and those with negative antibodies.Iodine intake assessed by UIC in Japanese pregnant women is regarded as sufficient and not excessive according to World Health Organization criteria. Although the data are local, our results provide additional information on the reference range for UIC throughout gestation in iodine-sufficient areas.

A surgically treated idiopathic giant-cell granuloma of the pituitary in a 48-year-old man is described. Relative to previously reported cases, this case was unusual both clinically and histologically. Diabetes insipidus was the initial, and a prominent clinical, manifestation. Histological studies showed caseating granuloma or fibrosis in addition to a typical giant-cell granuloma. This is the first published documentation of the association of caseous necrosis in a patient diagnosed as having idiopathic giant-cell granuloma of the pituitary.Endocr Pathol 4:169-173, 1993.

In this study, we compared the clinical and endocrinological characteristics, neuroimaging findings, surgical outcome, and conventional histological findings (including immunohistochemistry) with the electron microscopic appearance of 31 growth hormone (GH)-producing adenomas. By electron microscopy, these 31 tumors were divided into 23 densely granulated somatotroph adenomas (DG adenomas) and 8 sparsely granulated somatotroph adenomas (SG adenomas). SG adenomas more frequently affected younger women, but no significant correlation was found between the adenoma type and the characteristic signs and symptoms of acromegaly, the incidence of diabetes mellitus or hypertension, or the basal serum GH and insulin-like growth factor I levels. A distinct response of GH to thyrotropin-releasing hormone, bromocriptine, or GH-releasing hormone was significantly more common in patients with DG adenomas than in those with SG adenomas, whereas the incidence of a response to gonadotropin-releasing hormone or oral glucose was not significantly different between the two groups. An analysis of neuroimaging findings and surgical results indicated that SG adenomas were more likely to be macroadenomas with suprasellar extension or invasive tumors and had a lower surgical cure rate. However, postoperative radiotherapy seemed to be similarly effective in both types of adenoma to prevent a tumor recurrence and to reduce postoperative GH basal level in serum. Light microscopy showed that DG adenomas were mainly acidophilic and were immunopositive not only for GH but also for prolactin (43%), the beta subunit of thyroid-stimulating hormone (26%), and the alpha subunit of glycoprotein hormone (87%), whereas SG adenomas were almost all chromophobic and only revealed immunopositivity for GH.(ABSTRACT TRUNCATED AT 250 WORDS)

Silent somatotroph adenomas are defined as tumors showing morphological features consistent with GH production, but no clinical evidence of GH excess. We report here the case of a 46-yr-old woman with a large pituitary macroadenoma, slightly elevated serum GH levels, high serum insulin-like growth factor-I levels, and abnormal GH dynamics, but no acromegaly. The endocrinological abnormalities receded after transphenoidal surgery despite tumor persistence, as shown by neuroimaging. The reverse hemolytic plaque assay, performed for the first time in a silent GH cell adenoma, demonstrated that the number of GH cells releasing GH and the amount of GH discharged from individual cells were less than those in clinically functioning somatotroph adenomas. Thus, it is conceivable that this tumor secreted only small quantities of GH and for only short periods, providing an explanation for the lack of acromegaly. It appears that silent somatotroph adenomas do not represent a distinct entity. It is more likely that there is a continuous spectrum from clinically functioning, sparsely granulated somatotroph adenomas with high serum GH levels to silent somatotroph adenomas with normal serum GH levels. The cause of the lack of GH oversecretion in silent GH cell adenomas has yet to be elucidated.

原発性副甲状腺機能亢進症は血中カルシウム値のスクリーニングから発見される場合が多い.効率よくスクリーニングを行うには, 1)検体のCa測定値からfree Ca indexを計算し,高値のものについて, 2) mPTHを測定し, 3) fee Ca濃度, mPTH双方とも高値の場合には,患者に来院してもらい,さらにfree Ca値の再測定とiPTHの測定を行って診断を確かめる.

Parathyroid hormone-related protein (PTHrP) was first identified in human malignant tumors associated with humoral hypercalcemia of malignancy. We immunohistochemically examined the distribution of PTHrP both in 7 normal parathyroid glands and in a 20 parathyroid adenomas. Sixty-five percent of parathyroid adenomas (13 cases) were positive for PTHrP, whereas only one normal parathyroid gland was positive for PTHrP in the area of transitional oxyphil cells. Many parathyroid adenomas (12 cases) were composed of both PTHrP-positive cells and--negative cells, and these two different type of cells showed a tendency to form nodules respectively in parathyroid adenoma. Although both chief cells and oxyphil or transitional oxyphil cells were positive for PTHrP in parathyroid adenoma, oxyphil or transitional oxyphil cells were more responsible for PTHrP production than chief cells. Chief cells are thought to produce parathyroid hormone mainly in parathyroid adenoma. On the other hand, little is known concerning the function and role of oxyphil or transitional oxyphil cells. Our results suggest that oxyphil or transitional oxyphil cells in parathyroid adenoma may have some functional roles different from those of chief cells through the production of PTHrP.

A case of disseminated cryptococcosis with features of primary adrenal insufficiency and meningitis in an immunocompetent host is presented. Despite antifungal chemotherapy, neither meningitis nor bilateral adrenal gland enlargement was improved. Aspiration biopsy of the adrenal gland revealed necrotic tissue with numerous fungi, suggesting that the adrenal glands were the focus of the persistent fungemia. Removal of bilateral adrenal glands led to improvement by making the patient more sensitive to antifungal chemotherapy.

Pharmacia HA 50R (Pharmacia) which enables direct measurement of serum hyaluronan concentration is evaluated for its convenience and accuracy.In this kit, HABP which has specific affinity for hyaluronan is radiolabelled with 125I as ligand assay is performed as radiometric assay.Intra and inter assay precision, linearity and recovery test give favorable results.It is confirmed that this kit is convenient and useful for measurement of serum hyaluronan concentration.

In a 30-year-old woman with amenorrhea due to hyperprolactinemia, serum PRL increased to twice the basal amount in response to growth hormone-releasing hormone (GHRH). Roentgenological studies revealed no pituitary adenoma but empty sella. Bromocriptine therapy normalized serum PRL and made the paradoxical response to GHRH disappear. The paradoxical response did not occur in any of eight other patients with hyperprolactinemia due to prolactinoma. Although this case is rare, GHRH stimulates PRL as well as GH release remarkably in some cases with hyperprolactinemia without a GH-producing tumor.

A 77-year-old man complained of headache, dizziness and tactile hallucination. Based on those clinical signs and the findings of computed tomography scanning and magnetic resonance imaging, he was diagnosed as having pituitary adenoma. Clinical signs and symptoms of Cushing's disease had not been apparent because of the occurrence of the disease at an old age. An increase in serum cortisol and adrenocorticotropic hormone indicated the presence of Cushing's disease. Physical findings obtained thereafter were also compatible with the disease. While the patient was being prepared for surgery, pituitary apoplexy and intraventricular hemorrhage occurred. Massive ascites appeared as a result of tuberculous peritonitis. In spite of treatment for these complications, his general condition progressively deteriorated and he died 39 days after the intraventricular hemorrhage. This case presents the difficulty in the treatment of masked Cushing's disease in the elderly population.

The authors report a rare case of intrasellar gangliocytoma without endocrinopathy. The tumor, removed by transsphenoidal surgery, exhibited immunoreactivities for VIP and galanin in the cytoplasm of several nerve cells, a-subunit, somatostatin, and serotonin in the cytoplasm of few nerve cells. Our case indicates that gangliocytomas can produce unusual combinations of peptides which, despite their known biologic activity, do not invariably cause clinical abnormalities.

甲状腺機能亢進症は臨床症状から診断できる場合が多いが, 60才以上では症状が現われにくくmasked hyperthyroidismの形をとることがしばしばあるし,甲状腺機能低下症は初期には臨床症状を呈さない.したがって甲状腺疾患の存在を疑って採血して検査してみる心がけが常に必要で,このことはすでに何らかの疾患と診断されている患者についても常に必要なことである.

We report on the clinical and molecular findings in 25 males and three females with Kallmann syndrome (KS) aged 10-53 yr. Ten males were from five families, and the remaining 15 males and three females were apparently sporadic cases. Molecular studies were performed for Kallmann syndrome 1 (KAL1) and fibroblast growth factor receptor 1 (FGFR1, also known as KAL2) by sequence analysis for all the coding exons, by PCR-based deletion analysis, and by fluorescence in situ hybridization (FISH) analysis, showing six novel and two recurrent intragenic KAL1 mutations in seven familial and four sporadic male cases and two novel intragenic FGFR1 mutations in two sporadic male cases. In addition, submicroscopic deletions at Xp22.3 involving VCX-A, STS, KAL1, and OA1 were identified in three familial cases and one sporadic male case affected by a contiguous gene syndrome. Clinical assessment in the 15 males with KAL1 mutations showed normal and borderline olfactory function in two males and right-side dominant renal lesion in seven males, in addition to variable degrees of hypogonadotropic hypogonadism (HH) in all the 15 males and olfactory dysfunction in 13 males. The two males with FGFR1 mutations had HH and anosmia and lacked other features. Clinical features in the remaining 11 cases with no demonstrable KAL1 or FGFR1 mutations included right renal aplasia in one female, cleft palate in one male, cleft palate and perceptive deafness in one male, and dental agenesis and perceptive deafness in one male, in addition to a variable extent of HH and olfactory dysfunction. The results suggest the following: 1) KAL1 mutations might be more prevalent in the Japanese patients than previously estimated in the Caucasian patients and can be associated with apparently normal olfactory function; 2) FGFR1 mutations account for approximately 10% of KS patients, as previously reported in the Caucasian patients, and can result in HH and olfactory dysfunction-only phenotype; and 3) renal aplasia, which is characteristic of KAL1 mutations, and cleft palate and dental agenesis, which are characteristic of FGFR1 mutations, can occur in patients without KAL1 and FGFR1 mutations.

Background: Goiter prevalence in school-age children is an indicator of the severity of iodine deficiency disorders (IDDs) in a population. In areas of mild-to-moderate IDDs, measurement of thyroid volume (Tvol) by ultrasound is preferable to palpation for grading goiter, but interpretation requires reference criteria from iodine-sufficient children. Objective: The study aim was to establish international reference values for Tvol by ultrasound in 6–12-y-old children that could be used to define goiter in the context of IDD monitoring. Design: Tvol was measured by ultrasound in 6–12-y-old children living in areas of long-term iodine sufficiency in North and South America, central Europe, the eastern Mediterranean, Africa, and the western Pacific. Measurements were made by 2 experienced examiners using validated techniques. Data were log transformed, used to calculate percentiles on the basis of the Gaussian distribution, and then transformed back to the linear scale. Age- and body surface area (BSA)–specific 97th percentiles for Tvol were calculated for boys and girls. Results: The sample included 3529 children evenly divided between boys and girls at each year (x SD age: 9.3 1.9 y). The range of median urinary iodine concentrations for the 6 study sites was 118– 288 g/L. There were significant differences in age- and BSAadjusted mean Tvols between sites, which suggests that populationspecific references in countries with long-standing iodine sufficiency may be more accurate than is a single international reference. However, overall differences in age- and BSA-adjusted Tvols between sites were modest relative to the population and measurement variability, which supports the use of a single, site-independent set of references. Conclusion: These new international reference values for Tvol by ultrasound can be used for goiter screening in the context of IDD monitoring. Am J Clin Nutr 2004;79:231–7.

OBJECTIVE Sixty-one of 83 patients with acromegaly treated between 1969 and 1993 were analysed retrospectively to clarify which early postoperative factors were significant predictors of a successful long-term outcome and which preoperative factors significantly influenced the early postoperative results. PATIENTS Of the 61 patients, 30 were operated on before 1987 and 31 afterwards. A successful long-term surgical outcome was defined as a long-term mean basal GH level < 6 mU/l (comparable to < 3 micrograms/l), a normal IGF-I level, and normal GH dynamics. RESULTS Overall, 59% of patients (37% before 1987 and 81% after) had an early postoperative mean basal GH level < 6 mU/l, and 56% (29% before 1987 and 77% after) met all three of the specified criteria for a successful long-term surgical outcome. Statistical analysis confirmed that GH dynamics and postoperative mean basal GH level < 6 mU/l were significant predictors of the long-term surgical outcome, whereas the postoperative IGF-I level alone was not. On the other hand, abnormal preoperative GH dynamics were normalized in all patients with a postoperative mean basal level < 6 mU/l. In addition, there were no patients showing an unsuccessful long-term outcome in those associated with both the early postoperative mean basal GH level < 6 mU/l and normalization of the IGF-I level. Therefore, measurement of the early postoperative mean basal GH level and the IGF-I level may be an economical and simple guide to predict the long-term surgical outcome. Moreover, multivariate analysis indicated that cavernous sinus invasion was an independent significant factor influencing the early postoperative outcome. CONCLUSIONS Successful long-term surgical outcome may be predicted if early postoperative mean basal GH level is reduced to < 6 mU/l (< 3 micrograms/l) and IGF-I level becomes normal. This study also confirms that early diagnosis and treatment by an experienced endocrinologist and neurosurgeon can improve the operative results in patients with acromegaly.

Human interferon beta (IFN-beta) has been used for the treatment of patients with benign and malignant astrocytomas. The effect of IFN-beta on pituitary function, however, has not been precisely evaluated before. In this study the serum levels of various anterior pituitary hormones including GH, PRL, ACTH, and TSH were measured to determine the effects of IFN-beta on pituitary endocrine function in 19 consecutive glioma patients receiving IFN-beta. Daily doses of 3 x 10(6) U of IFN-beta were administered as a 30-min intravenous drip infusion beginning at 0800 h every morning during the first week and then 4 times a week for additional 6 weeks. Blood samples were taken on the day prior to administration as controls (0900 h and 1500 h), and on the first day of administration (0900 h and 1500 h) and after 7 days of administration (0900 h) in order to determine the acute and chronic or integrated effects of IFN-beta on the above pituitary hormones. No significant change in serum concentrations of any of the pituitary hormones examined was observed, suggesting that human natural IFN-beta used for the treatment of gliomas has no significant effect on the secretion of these hormones from the pituitary in these patients.

We report a case of a 25-year-old man with Cushing’s syndrome due to an ACTH and CRH-producing thymic carcinoid. Immunohistology and radioimmunoassay demonstrated CRH and a lesser amount of ACTH in the resected primary tumor. After a symptom-free period, the tumor recurred, and the patient died. Tumor obtained at autopsy contained mainly ACTH and lesser quantities of CRH. We conclude that this thymic carcinoid initially produced mainly CRH and then transformed to secrete mainly ACTH, suggesting that endocrine tumors may change their functional phenotype.