Clinical trials of human GH (hGH) therapy in Turner's syndrome were started in 1986. Between 1986 and 1990. 362 patients were enrolled; 115 were treated for more than 6 years. The age at the start of treatment ranged from 5 to 18 years (mean 10 years). Fifty-one patients received hGH at a weekly dosage of 0.5 IU/kg and 64 received 1.0 IU/kg by daily s.c. injection. Both treatment groups showed a statistically significant growth increase during the initial 4 years of treatment. The rate of increase in height was significantly greater for the initial 2 years with the high dose than with the low dose. The increases in height over 6 years of treatment (expressed by S.D. score for chronological age) were 1.48 +/- 0.8 with 0.5 IU/kg per week and 1.80 +/- 1.0 with 1.0 IU/kg per week. To date, 260 patients have stopped GH therapy. In 32% of them, the height attained was above the -2 S.D. value for normal girls. In 27%, the growth rate was not sufficient when they stopped treatment. The mean final height (growth rate < or = 1.0 cm/year) of patients treated for more than 6 years was 142.2 +/- 6.5 cm (n = 15) with 0.5 IU/kg per week, and 144.3 +/- 3.9 cm (n = 15) with 1.0 IU/kg per week. The adult height was improved by GH treatment, although final height did not differ statistically between the two dose regimens. No remarkable adverse events occurred during the treatment. These results indicate that hGH treatment improves the final height in patients with Turner's syndrome.
K Takano, M Ogawa, T Tanaka, K Tachibana, K Fujita and N Hizuka
M Honda, T Tsukada, H Tanaka, K Maruyama, K Yamaguchi, T Obara, T Yamaji and M Ishibashi
OBJECTIVE: To determine whether familial isolated hyperparathyroidism (FIHP) is a variant of multiple endocrine neoplasia type 1 (MEN1) we analyzed the MEN1 gene in such a kindred. DESIGN AND METHODS: The study included the 70-year-old proband and nine relatives. Blood was drawn for biochemical evaluation and germline mutation analysis by direct sequencing of the MEN1 gene amplified by PCR. A hyperplastic parathyroid gland obtained from a family member served for a loss of heterozygosity (LOH) study. RESULTS: Three members from two generations in this kindred were found to have primary hyperparathyroidism, while none had clinical or biochemical evidence of MEN1, MEN2 or hyperparathyroidism--jaw tumor syndrome. Analysis of germline DNA in the proband showed a missense mutation (GGC-->GAC) at codon 305 in exon 7 of the MEN1 gene that predicts an amino acid change from glycine to aspartic acid (G305D). This mutation segregated with primary hyperparathyroidism in the kindred, and, in addition, there were two asymptomatic mutant-gene carriers at relatively advanced ages. In contrast, the mutation was not detected in genomic DNA from five unaffected individuals and from 50 healthy subjects. The LOH study showed a loss of the wild-type allele, which confirmed that a functional defect of the MEN1 gene product, menin, is etiological for FIHP. CONCLUSIONS: FIHP is a genetically heterogeneous disease with a subset linked to MEN1, most likely representing a variant of MEN1. The late onset and the reduced penetrance of disease found in this kindred may be related to the site and the type of mutation, although the precise mechanism involved is unknown at present.
H. Tanaka, H. Manabe, K. Koshiyama, Y. Hamanaka, K. Matsumoto and T. Uozumi
Quantitative determinations of urinary 17-ketosteroids (17-KS) and 17-hydroxycorticosteroids (17-OHCS) were made in 17 males and 8 females before and for 7 days following moderate to major surgery.
The operation caused a marked rise in the excretion of total 17-OHCS. On the other hand, a significant decrease in the excretion of the total 17-KS was found following surgery. The postoperative decrease resulted from a significant decrease in the excretion of C19O2- 17-KS, since the urinary C19O3-17-KS remained almost unchanged following the operation. The postoperative decrease was shown to be of a higher degree in males since the decrease in the excretion of aetiocholanolone and androsterone was more marked in males than in females. Contrary to this, the excretion of both C19O3-17-KS and C19O2-17-KS increased following ACTH injection. From the result, it seems justifiable to assume that the secretion of androgen from the testes may decrease rapidly following operation. It was also demonstrated that the ratio of aetiocholanolone to androsterone increased postoperatively as did the ratio of THF to alloTHF. Furthermore, the ratios of THE to THF and E to F were found to be significantly decreased following surgery.
Y. Monden, K. Koshiyama, H. Tanaka, S. Mizutani, T. Aono, Y. Hamanaka, T. Uozumi and K. Matsumoto
Plasma testosterone levels were determined in 42 male patients both before 1, 2, 3, 4, 6, 8 and 12 weeks following pulmonary lobectomy. The plasma LH was measured in 13 of the 42 patients. There was a significant fall in the plasma levels of testosterone 1, 2 and 3 weeks after the pulmonary lobectomy but the levels returned to the control values from the fourth post-operative week onward. On the other hand, the level of plasma LH increased significantly one week after the operation when the plasma testosterone showed the most marked decrease.
The urinary 17-KS and 17-OHCS were measured in 27 of the 42 male patients, both before and 1, 4, 8 and 12 weeks after the operation. The total 17-KS was found to be significantly decreased 1, 4 and 8 weeks after the operation. The post-operative decrease resulted from a significant decrease in the excretion of C19O2-17-KS on the seventh postoperative day but thereafter the decrease mainly resulted from a decrease in C19O3-17-KS.
It is suggested that testosterone secretion from the testes seems to decrease for 3 weeks after major surgery. The decrease in the excretion of 17-KS observed after this post-operative period is caused by a decrease in the excretion of metabolites from adrenal androgens.
K Tanaka, T Otsuki, H Sonoo, Y Yamamoto, K Udagawa, H Kunisue, I Arime, S Yamamoto, J Kurebayashi and K Shimozuma
OBJECTIVE: To investigate the levels of expression of the sodium iodide symporter (NIS) and three differentiation markers (thyroglobulin (Tg), thyroid peroxidase (TPO) and thyrotrophin receptor (TSH-R)) in 35 patients with primary (n=31) or recurrent (n=4) papillary thyroid carcinoma, and to compare the findings with clinical data. METHODS: We performed a multiplex semi-quantitative RT-PCR to analyse the relative levels of expression of Tg, TPO and TSH-R mRNAs, and a separate semi-quantitative RT-PCR for NIS mRNA. RESULTS: Tg, TPO and TSH-R mRNAs were expressed in all the patients, whereas NIS mRNA was expressed in all but eight. Analysis of the expression of the differentiation markers in all patients showed a significant correlation among Tg, TPO and NIS. With regard to the relationship between the expression of each gene and the MACIS score, there was significant correlation only for the Tg gene (P<0.05). CONCLUSIONS: The levels of expression of NIS mRNA correlated significantly with those of Tg and TPO mRNAs, but not with those of TSH-R mRNA. The relationship with clinical stage and prognostic score, however, varied among these differentiation markers.
N Nagata, J Kato, K Kitamura, M Kawamoto, N Tanaka, T Eto and M Takasaki
Adrenomedullin (AM), a potent vasodilator peptide, has been shown to act within the central nervous system to modulate fluid and electrolyte balance. AM-immunoreactive cells have been found in the anterior pituitary gland and the choroid plexus of humans. In addition, AM activity has been implicated in the regulation of maternal circulation during pregnancy. To determine the relationship between AM concentration in the cerebrospinal fluid (CSF) and plasma, we measured AM levels in CSF and plasma of pregnant (group P, n = 12) and non-pregnant (group NP, n = 10) women scheduled to undergo gynecologic or obstetric surgery. In both groups, the concentration of AM in the plasma exceeded that in the CSF. Plasma AM concentration was significantly higher in pregnant than non-pregnant women (17.3+/-5.8 vs 5.1+/-1.4 pmol/l, mean +/- S.D.; P<0.01), whereas CSF AM concentration did not differ between the two groups (1.3+/-0.9 and 0.9+/-0.4 pmol/l in groups P and NP respectively). No significant correlation was found between AM concentrations in the CSF and plasma. The present findings suggest that AM is present in the CSF and that its concentration in the CSF is regulated independently from that in the plasma.
K. Shima, N. Sawazaki, R. Tanaka, S. Morishila, S. Tarui and M. Nishikawa
In order to assess the secretory capacity of the pancreatic alpha and beta cells in patients with hyperthyroidism, the plasma glucagon and insulin responses to 1-arginine and insulin-induced hypoglycaemia in 12 patients were compared with those in 6 normal subjects. The response of beta cell to hypoglycaemia was evaluated by measuring the decrease in plasma C-peptide immunoreactivity (CPR) level.
There was a negligible rise in blood glucose and plasma insulin levels in the patients, whereas a significant increase occurred in normal subjects during the arginine infusion. Although no difference in the fasting plasma glucagon concentration between the two groups was found, 30 min after the beginning of the arginine infusion, the plasma glucagon levels rose to a peak of 252 ± 35 pg/ml in the patients, a value significantly lower than 387 ± 53 pg/ml in the normal subjects. The insulin-induced hypoglycaemia caused no significant difference in the peak values of plasma glucagon between the two groups. There was a significant fall in plasma CPR after the insulin injection in both groups but the per cent decrement was rather greater in the patients than in the normal subjects.
These results suggest that the pancreatic alpha and beta cells in hyperthyroidism have a functional defect in response to 1-arginine but not to insulin-induced hypoglycaemia. The mechanism involved in these disorders is discussed.
Y. Okada, T. Onishi, K. Tanaka, S. Morimoto, M. Tsuji, K. Watanabe, A. Okazaki, T. Takeuchi and Y. Kumahara
Prolactin (PRL) and TSH responses to TRH, chlorpromazine (CPZ) and L-DOPA were studied in 23 children (15 male and 8 female) with human growth hormone (HGH) deficiency. Eight patients (group I) showed normal PRL response to TRH and CPZ but TSH response to TRH was delayed in 4 of this group. Twelve patients (group II) had normal (4 patients) or higher (8 patients) baseline PRL level and showed lower PRL response to CPZ than that to TRH. TSH response to TRH was normal in 3, blunted in 1, and delayed in 8 patients. Three patients (group III) had no PRL response to either TRH or CPZ. TSH response to TRH was normal in 1 but blunted in 2 patients. Of 8 patients with a higher baseline PRL level (group II and III), L-DOPA suppressed PRL secretion to less than 50 % of the initial value in 7 patients, but not in 1 patient, in whom the diagnosis of hypothalamic tumour was established on brain surgery following these examinations. These results suggest that hypothalamic disorders are involved in more than half of 23 children with HGH deficiency.
T Akamizu, K Takaya, T Irako, H Hosoda, S Teramukai, A Matsuyama, H Tada, K Miura, A Shimizu, M Fukushima, M Yokode, K Tanaka and K Kangawa
OBJECTIVE: It has been demonstrated that ghrelin plays a major role in the regulation of GH secretion and food intake. These actions make ghrelin a strong candidate for the treatment of GH deficiency, anorexia and cachexia. However, only preliminary studies have been performed to assess ghrelin administration in humans. In this study, we have conducted a double-blind, randomized, placebo-controlled trial to investigate the pharmacokinetics, safety, and endocrine and appetite effects of ghrelin in young healthy volunteers. DESIGN: Eighteen male volunteers were randomly assigned into three groups of six subjects: low- and high-dose ghrelin groups, who received intravenous injections of 1 and 5 microg/kg ghrelin (acylated form) respectively, and a placebo group who were injected with mannitol instead of ghrelin. RESULTS: Acylated ghrelin disappeared more rapidly from plasma than total ghrelin, with elimination half life (t(1/2)) of 9-13 and 27-31 min respectively. The number of subjects that experienced adverse effects did not significantly differ among the three groups, and all adverse effects were transient and well tolerated. Both the low and high doses of ghrelin strongly stimulated GH release (peak plasma concentration (C(max,0-90 min)): 124.2+/-63.9 and 153.2+/-52.2 ng/ml for 1 and 5 microg/kg ghrelin respectively). Slight alterations of blood glucose and insulin levels after the injection were observed. Although not statistically significant, ghrelin administration tended to increase hunger sensation in a dose-dependent manner. CONCLUSIONS: These results suggest that ghrelin is safe, and that clinical trials may be started to assess the usefulness of ghrelin for the treatment of disorders related to GH secretion and appetite.
S Tanaka, KI Tatsumi, M Kimura, T Takano, Y Murakami, T Takao, K Hashimoto, Y Kato and N Amino
OBJECTIVE: Several reports have described antipituitary antibodies by immunofluorescent or immunoblotting methods in patients with lymphocytic hypophysitis. However, with the exception of the pituitary hormones, individual antigens specific for the pituitary gland have not been studied. To understand the pathogenesis of lymphocytic hypophysitis and to diagnose this disease efficiently, we studied the presence of autoantibodies against three pituitary-specific proteins, GH and two novel pituitary-specific proteins, namely, pituitary gland specific factor 1a (PGSF1a) and PGSF2. DESIGN: Seventeen patients with lymphocytic hypophysitis, all of whom had pituitary enlargement (5 with lymphocytic adenohypophysitis and 12 with lymphocytic infundibuloneurohypophysitis, including 3 of the latter group proven by biopsy), and 14 patients with hypopituitarism without pituitary enlargement (10 with isolated ACTH deficiency and 4 with idiopathic TSH deficiency) were studied, and compared with 11 patients with non-functioning pituitary macroadenoma, 31 patients with other autoimmune diseases, and 36 healthy controls. METHODS: The presence of each antibody was studied by radioligand assay using recombinant human (35)S-labeled protein. RESULTS: Three (18%) patients with lymphocytic hypophysitis having pituitary enlargement, five (36%) patients with hypopituitarism without pituitary enlargement and three (9.7%) patients with other autoimmune diseases were positive for one or more of the antibodies studied. CONCLUSIONS: Anti-human GH, anti-PGSF1a, and anti-PGSF2 antibodies were detected in patients with lymphocytic hypophysitis and other hypopituitarism, but were not detected in patients with non-functioning pituitary macroadenoma. Detection of these antibodies may be useful for the diagnosis of lymphocytic hypophysitis.