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H Kaji and K Chihara

OBJECTIVES: The direct causes of death in Japanese patients with hypopituitarism remain unclear. In this study, the direct causes of death were investigated and compared between Japanese patients with hypopituitarism from a nation-wide autopsy database and an age- and gender-matched control population from national reports. SUBJECTS: Three hundred and ninety-one subjects with hypopituitarism who had died were selected from a nation-wide autopsy database (1984-1993). The ratios of each cause of death among the age- and gender-matched control population were derived from national reports. RESULTS: In subjects with hypopituitarism, an increased relative frequency of death from cerebrovascular diseases (male; 2.02 (95% confidence interval (CI) 1.45-2.82), female; 1.73 (95% CI 1.18-2.52)) was found. In particular, the relative frequency of death from cerebral hemorrhage was 4.60 (95% CI 2.95-7.17) in male and 4.80 (95% CI 2.90-7.94) in female subjects with hypopituitarism. Unexpectedly, a decreased relative frequency of death from all heart diseases (male; 0.439 (95% CI 0.277-0.696), female; 0.267 (95% CI 0.149-0.478)) was found in subjects with hypopituitarism, although there was no difference between subjects with hypopituitarism and controls in the frequency of death from ischemic heart disease. CONCLUSIONS: These results provide useful information for the long-term care of Japanese patients with hypopituitarism.

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H Kaji, S Saito, K Shitsukawa, M Irahara and T Aono

OBJECTIVE: To clarify the mechanism of the suppressive effect of 2-buten-4-olide (2-B4O), an endogenous feeding suppressant, on the pulsatile secretion of luteinizing hormone (LH), by studying whether endogenous opioid peptides are involved in this suppressive effect. METHODS: Using ovariectomized (ovx) rats, blood samples were taken every 6 min for 2 h after administration of 2-B4O or saline into the third cerebroventricle (3V) and sequential i.v. injection of naloxone (0. 5 mg/kg per h) or saline. Rats were divided into three experimental groups: group 1: 3V saline + i.v. saline (control); group 2: 3V 2-B4O + i.v. saline; group 3: 3V 2-B4O + i.v. naloxone. Serum LH concentrations were determined by double-antibody RIA. To determine whether 2-B4O affected the biosynthetic activity of the opioidergic neurons within the ovx rat arcuate nucleus, we measured the concentrations of pro-opiomelanocortin (POMC) mRNA, a precursor of beta-endorphin, in the rostral arcuate nucleus using non-radioactive in situ hybridization and a computerized image-analysis system. RESULTS: 2-B4O significantly suppressed the pulse frequency of LH (group 2: 1.5+/-0.33 pulses/2 h, group 1: 2.43+/-0.2 pulses/2 h; P < 0.05), but naloxone blocked its suppressive effect and restored the pulse frequency (group 3: 3.29+/-0.36 pulses/2 h, group 2: 1.5+/-0.33 pulses/2 h: P < 0.01). There were no significant changes in the mean LH concentrations and amplitude. Furthermore, 2-B4O significantly stimulated the expression of POMC mRNA in the rostral arcuate nucleus. CONCLUSION: These results suggest that 2-B4O may impair the pulsatile secretion of LH by activating the opioid pathway within the hypothalamus.

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M Kanatani, T Sugimoto, H Kaji, K Ikeda and K Chihara

BACKGROUND: Although there have been some case reports suggesting that bone in patients with pseudohypoparathyroidism (PHP) might respond to parathyroid hormone (PTH), no information is available as to whether serum PTH concentration is related to bone metabolic markers or to bone mineral density (BMD) in PHP. OBJECTIVE: To address these relationships, by comparing intact serum PTH, bone metabolic markers and BMD in patients with PHP with those in patients with idiopathic hypoparathyroidism (IHP) and postoperative hypoparathyroidism (OHP). METHODS: Intact serum PTH, bone metabolic markers (osteocalcin, tartrate-resistant acid phosphatase, pyridinoline, deoxypyridinoline) and BMD by dual-energy X-ray absorptiometry or single-photon absorptiometry were measured in patients with PHP Ia (n=2) and PHP Ib (n=8). The results were compared with those in patients with IHP (n=5) and OHP (n=14). RESULTS: All bone metabolic markers measured were present in significantly greater amounts in patients with PHP Ib than in those with IHP+OHP. The Z score (standard deviation of average BMD at each age) of the BMD of femoral neck was significantly lower in patients with PHP Ib than in those with IHP+OHP. The Z scores of BMD of lumbar spine and radius were also lower in patients with PHP Ib than in those with IHP+OHP, but the difference was not significant. Moreover, the intact serum PTH concentrations were significantly and positively related to bone metabolic marker levels in all patients, and the intact serum PTH concentrations were significantly and negatively related to BMD of lumbar spine in PHP patients. CONCLUSIONS: These results suggest that PTH stimulates bone turnover in PHP Ib patients, resulting in a relatively lower BMD in PHP Ib patients than in IHP+OHP patients. The present study indicates that bones of most cases of PHP could respond to PTH.

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T Ogata, K Muroya, H Ohashi, H Mochizuki, T Hasegawa and M Kaji

OBJECTIVE: A sex determining gene(s) has been mapped to a approximately 700 kb region distal to the exons of DMRT1 on 9p. The aim of this study was to examine gonadal developmental status in XX patients hemizygous for the 9p sex determining region. DESIGN: Clinical and molecular studies were performed in an 8-year-old girl with 46,XX,del(9)(p22) (case 1) and in a 2-year-old girl with 46,XX,del(9)(p23) (case 2). METHODS: Ovarian function status was assessed by gonadotrophin-releasing hormone (GnRH) tests. Hemizygosity for the sex determining region was examined by fluorescence in situ hybridisation and microsatellite analyses for a total of 17 loci on distal 9p. RESULTS: GnRH tests indicated mild gonadotrophin hyper responses in both cases (case 1: follicle stimulating hormone 9.2-->22.7 IU/l, luteinising hormone 0.7 --> 16.6 IU/l; case 2: follicle stimulating hormone 7.6 --> 38.2 IU/l, luteinising hormone 0.6 --> 9.4 IU/l). Molecular studies showed hemizygosity for the 9p sex determining region in both cases. CONCLUSIONS: The results, in conjunction with previous reports describing sex development in XX and XY patients hemizygous for the 9p sex determining region, imply that haploinsufficiency of the 9p sex determining gene(s) primarily hinders the formation of the indifferent gonad, leading to a wide range of testicular or ovarian development.

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M Kishimoto, Y Okimura, M Fumoto, G Iguchi, K Iida, H Kaji and K Chihara

OBJECTIVE: Genetic abnormalities of the pituitary specific transcription factor, Pit-1, have been reported in several patients with GH, prolactin (PRL) and TSH deficiencies. The most common is a mutation altering an arginine to a tryptophan in codon 271 (R271W) in one allele of the Pit-1 gene. According to the previous in vitro expression study, R271W acted as a dominant negative inhibitor of the wild type to activate the GH promoter. However, healthy carriers with this mutation, who should be affected by the dominant negative effect of R271W, have also been reported. The aim of this study was to clarify in more detail the function of this mutant form of Pit-1. METHODS: Transcriptional activity of R271W for the expression of Pit-1-associated genes was investigated in COS7 cells with the aid of transient transfection assays. The 1.8 kb rat GH, 0.6 kb rat PRL or 1.9 kb rat PRL 5'-flanking regions were inserted upstream of the luciferase reporter gene and were used for functional analysis of R271W. Another reporter gene containing seven Pit-1 responsive elements was also used. The same experiments were also performed using JEG3 and CHO cells. RESULTS: We could not confirm the dominant negative effect of R271W on wild type Pit-1. Furthermore, our expression study revealed that R271W could activate the promoters of GH and PRL genes to levels similar to the wild type. CONCLUSION: Taken together with the evidence that phenotypically normal cases have been reported with this mutation, our results deny the relationship between R271W and combined pituitary hormone deficiency.

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M Murata, H Kaji, I Mizuno, T Sakurai, K Iida, Y Okimura and K Chihara

OBJECTIVES: Increased carotid intima-media thickness (IMT) has been reported among Caucasian adult GH-deficient (AGHD) patients, but not Japanese. Also, it is known that the clinical and biochemical characteristics of AGHD patients are somewhat different based on the onset of the disease in either childhood or adult life. Nevertheless, there has been no study comparing the magnitude of the deviation of their IMT from normal subjects between child-onset (CO) and adult-onset (AO) patients in terms of Z score. The aim of this study, therefore, was first to examine whether Japanese AGHD patients have a risk of early development of atherosclerosis similar to Caucasian patients and secondly to assess the difference in the onset and in progression of atherosclerosis. DESIGN AND SUBJECTS: Thirty-four patients (17 CO-AGHD, age 29+/-7 Years, body mass index (BMI) 24+/-3.8 kg/m(2) and 17 AO-AGHD, age 48+/-12 Years, BMI 23+/-3.6 kg/m(2)) and 34 age- and sex-matched healthy controls (17 CO controls and 17 AO controls) were enrolled in the present study. Blood samples were taken for measurements of lipids, lipoproteins and IGF-I. Subsequently, patients underwent IMT assessment. RESULTS: CO patients were significantly younger than AO patients. The duration of GH-deficiency in CO patients was significantly longer than that in AO patients. Serum triglyceride (TG) was significantly higher in CO patients than in CO controls (P<0.05). Serum total cholesterol and TG were significantly higher in AO patients than in AO controls (P<0.01). The IMT was significantly greater in CO and AO patients (0.82+/-0.08 and 0.79+/-0.03 mm) than in CO and AO controls (0.59+/-0.02 and 0.68+/-0.03 mm, P<0.01 and P<0.01 respectively). There was no significant difference in raw values of IMT between CO and AO patients. However, the Z score of IMT calculated using normal Japanese IMT values was significantly higher in CO than in AO patients (2.07+/-0.68 vs 0.35+/-0.48, P<0.05). CONCLUSIONS: These findings suggest that GH deficiency appears to increase an atherosclerotic risk in Japanese AGHD patients, as with Caucasians, and to cause more extensive IMT thickening in CO-AGHD than AO-AGHD patients.

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T Sugimoto, H Kaji, D Nakaoka, M Yamauchi, S Yano, T Sugishita, DJ Baylink, S Mohan and K Chihara

BACKGROUND: There has been increasing evidence that the growth hormone (GH)-IGF-I axis plays an important part in the maintenance of bone mass. However, controversy still exists as to the effect of GH treatment on bone mineral density (BMD) in elderly patients with osteoporosis. OBJECTIVE: To investigate the effect of low-dose GH treatment on markers of body composition and bone turnover, serum concentrations of IGF-I and IGF-binding proteins (IGFBPs), and BMD at the radius and lumbar spine in eight elderly Japanese women with osteoporosis. METHODS: Participants were treated with GH as a single daily subcutaneous injection (0.125 IU/kg per week; 0.00595 mg/kg per day) for 48 weeks. RESULTS: Markers of bone formation and bone resorption were both increased up to 24 weeks of GH treatment. The bone formation markers remained increased during GH treatment, whereas the bone resorption markers returned to baseline values after 24 weeks of GH treatment. GH treatment caused a rapid (within 2 weeks) and sustained increase in serum IGF-I concentration. As for IGFBPs, serum concentrations of IGFBPs-2, -3 and -4 did not change significantly during GH treatment. In contrast, GH treatment caused a gradual increase in serum IGFBP-5 concentration, with a significant increase seen 48 weeks after the start of GH treatment. Radial BMD seemed to be increased during the late period of GH treatment, although the change was not significant. Lumbar BMD did not change during GH treatment. GH treatment caused a significant increase in hand grip strength. None of the GH-treated participants had new fractures and side effects such as edema and joint pain. Radial BMD was significantly increased after discontinuation of GH treatment for another 48 weeks and a similar tendency was observed at the lumbar spine (7.1+/-2.3% above pretreatment values for the radius and 3.6+/-2.0% for the lumbar spine). CONCLUSIONS: Low-dose GH treatment attenuated the decrease in muscle strength and bone mass in elderly women without side effects, although changes in nutrition and exercise might affect BMD. The present findings provide useful information regarding the use of low-dose GH treatment in elderly women with osteoporosis.

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R Takeno, Y Okimura, G Iguchi, M Kishimoto, T Kudo, K Takahashi, Y Takahashi, H Kaji, M Ohno, H Ikuta, Y Kuroda, T Obara, H Hosoda, K Kangawa and K Chihara

OBJECTIVE: Ghrelin is a potent peptide stimulating GH secretion. Besides its direct action on the pituitary, ghrelin has been reported to stimulate GH release via the vagal afferent nerve in rats. To examine the involvement of vagal nerve in ghrelin-induced GH secretion in humans, GH responses to ghrelin were compared between vagotomized patients with gastrectomy and normal subjects. METHODS: Ghrelin (0.2 microg/kg) or GHRH (1 microg/kg) was administered intravenously in vagotomized patients and normal subjects on separate days, and plasma GH responses to the stimuli were examined. RESULTS: Ghrelin caused a significant plasma GH rise in both vagotomized patients and normal subjects. Peak GH levels in vagotomized patients (37.5+/-16.9 ng/ml) were not different from those in normal subjects (29.9+/-23.1 ng/ml). The areas under the curve of GH response to ghrelin did not differ between the two groups. GHRH also increased GH levels, and peak GH levels and areas under the curve after GHRH stimulation were also comparable between vagotomized patients and normal subjects. CONCLUSIONS: In the present study, the involvement of the afferent vagal nerve in ghrelin-induced GH secretion was not confirmed in humans.