Recently, the growth hormone secretagogue receptor (GHS-R) cDNA has been isolated from the pituitary and hypothalamus. To evaluate the regulation of human (h) GHS-R gene expression, we cloned the hGHS-R gene containing the 5-flanking region of 0.6 -2.9 kilobase pairs. Analysis of the hGHS-R transcripts with 5-rapid amplification of cDNA ends suggested that the putative transcription initiation site was approximately ؊453 base pairs upstream of the translation initiation site (؉1). There is no typical TATA, CAAT, or GC box but an initiator-like sequence and putative binding sites for several transcription factors around the putative transcription start site. The 5-flanking region inserted into a luciferase reporter vector had promoter activity in GH 3 cells but had activity indistinguishable from background in HeLa or EP1 cells. The hGHS-R promoter activity in GH 3 cells increased by deletion of nucleotides from ؊1224 to ؊734, whereas it was decreased by further deletion from ؊734 to ؊608. Knowledge of the promoter region of the hGHS-R gene will facilitate elucidation of its transcriptional control. Growth hormone (GH)1 secretion is regulated mainly by the hypothalamic stimulatory factor, GH-releasing hormone, and the inhibitory factor, somatostatin. On the other hand, GH secretagogues have been developed as a small synthetic peptide, GH-releasing peptide (1), and non-peptides, L-692,429 (2) and MK-0677 (3), with potent GH-secreting activity, especially in vivo and in humans. The recent cloning of the human, porcine (4), and rat (5) GHS receptor (GHS-R) cDNA has suggested an additional physiological regulation for GH release. GHS-R mRNA is expressed not only in the pituitary and hypothalamus but also in the hippocampus, pancreas (6), and neuroendocrine tumors (7), including human somatotropinomas and rat GH 3 cells (8). There are still only a few reports about the regulation of GHS-R expression. Bennett et al. (9) have recently reported that GHS-R expression in the hypothalamus was markedly increased in dw/dw dwarf rats and was downregulated in dw/dw rats treated with GH. They have also reported that GHS-R mRNA expression in the ventromedial nucleus of the hypothalamus was lower in male than in female rats.To understand the transcriptional regulation of the human GHS-R (hGHS-R) gene expression, we have cloned and characterized the 5Ј-flanking region of the hGHS-R gene. EXPERIMENTAL PROCEDURESMaterials and Cell Culture-All chemicals were obtained from Sigma. Fetal calf serum (FCS), horse serum, Ham's F-10, and Dulbecco's modified Eagle's medium were obtained from Life Technologies, Inc. Radionucleotides were obtained from Amersham Pharmacia Biotech (Tokyo, Japan). The rat GH-and prolactin (PRL)-producing pituitary tumor cell line GH 3 purchased from American Type Culture Collection (ATCC) was grown in Ham's F-10 medium with 15% horse serum and 2.5% FCS at 37°C in a humidified atmosphere of 5% CO 2 and 95% air. HeLa and EP-1 cells obtained from ATCC were grown in Dulbecco's modified Eagle's medium with 10% FCS in ...

Growth hormone (GH) deficiency (GHD) in adulthood leads to altered body composition, abnormal lipid, glucose, carbohydrate, and bone metabolism, decreased quality of life (QoL) and physical performance, and increased mortality due to cardiovascular disease [1][2][3]. Numerous studies have demonstrated that growth hormone replacement therapy, approved for use in adults in the United States and Europe in the mid-1990s [4], ameliorates many of the adverse consequences of GHD (reviewed in [5]). These studies have also increased our understanding of the baseline clinical characteristics of adults with GHD. , and liver disease (54 of 349; 15.5%) were the most common pre-existing conditions in Japanese adults with GHD. Quality of life was decreased in seven of the eight short form-36 domains in participants with GHD compared with age-and sex-matched healthy Japanese individuals. Our findings confirm that the clinical characteristics of Japanese adults with GHD are similar to those of Caucasian adults with GHD. Confirmation of these clinical characteristics will enhance the ability of clinicians to identify and treat Japanese adults with GHD.

Objective: To examine the responsiveness of quality of life (QoL) associated with changes in clinical indices relevant to GH deficiency (GHD) in Japanese hypopituitary adults. Design and methods: QoL was determined using the Short Form (SF)-36 in Japanese adults with adult-(AO; nZ27) or childhood-(CO; nZ37) onset GHD in a 24-week double-blind placebo-controlled study with a fixed GH dose, and a subsequent 48-week open-label extension study with GH doses individualized using serum IGF-I levels. Results: Baseline QoL was significantly decreased from the Japanese national reference in both onset types, more so in AO patients. Throughout the study, AO patients showed a trend for an increase in physical functioning and general health (PZ0.0564 and 0.0999 respectively), whereas CO patients showed no changes in these domains. Fat mass changes negatively correlated with the changes in physical functioning and general health in AO patients (rZK0.42 and K0.64 respectively), but to a lesser degree in CO patients (rZK0.36 and K0.32 respectively). CO patients displayed significant decreases in social functioning (PZ0.0305) and mental health (PZ0.0442) and a decreasing trend in bodily pain (PZ0.0769), although no correlation between these decreases and any measured clinical index was observed, except between changes in bodily pain and IGF-I levels (rZK0.43). Conclusions: QoL impairment was evident in Japanese adults with GHD, particularly in AO patients. In AO patients, general health and physical functioning domains were responsive to fat mass changes during GH treatment; this association was not evident in CO patients. These relationships between QoL and body composition warrant verification.European Journal of Endocrinology 156 637-645

Abstract. This large-scale observational study examined the long-term effectiveness and safety of growth hormone (GH) replacement therapy for adult GH deficiency (GHD) in Japanese clinical practice using the Hypopituitary Control and Complications Study database. The study included 402 GHD patients for safety analyses and a subset of 209 patients (149 adult-onset and 60 childhood-onset GHD patients) who had not previously received GH replacement therapy for the efficacy analyses. Data on clinical, metabolic, quality of life (QoL) characteristics, and all adverse events (AEs) were collected at baseline (start of GH treatment), 6 months, 1 year and 2 years. Over the observation period, there were improvements from baseline in insulin-like growth factor-I standard deviation scores (P < 0.001), although the changes in metabolic parameters were minimal. QoL (Short Form-36) Z-scores significantly increased from baseline in both onsettype groups for several subscale domains (P < 0.05). A total of 145 (36.1%) patients experienced ≥1 AE. Common AEs were hyperlipidaemia (2.7%) and hyperinsulinaemia (2.2%). Some patients experienced recurrent hypothalamic/pituitary tumour (events per 1000 patient-years: 2.78), new benign (0.93), malignant tumour (10.28) or other new tumour (0.93), new diabetes mellitus (7.45), and new stroke (3.71). Seven patients died during the observation period. Our safety findings are inconclusive about the associations between GH replacement and AEs, although the incidence of diabetes mellitus and cardiovascular events are similar to those reported in the Japanese general population. In conclusion, the key beneficial effects of GH replacement therapy for GHD are observed in routine clinical practice in Japan.

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The quality of life (QoL) of short children is an important issue that has been studied in Western countries, but not fully in Japan. We assessed the psychosocial profiles of Japanese children with short stature using the Japanese version of the Child Behavior Checklist (CBCL). A higher score in the CBCL means a lower QoL. A total of 116 children with idiopathic short stature (ISS) and 127 children with GH deficiency (GHD), aged 4 to 15 yr, were enrolled in the study. The total CBCL scores of the children in the GHD/ISS group were found to be higher than those of the normal children group. The QoL subscales for social problems and attention problems of the young (4–11 yr) children in the GHD/ISS group were significantly higher than those of the group of children of normal height. The proportion of children with GHD/ISS classified into the borderline/abnormal range was significantly higher than that of normal children. Children with ISS tended to have higher total scores and more subscale problems, and a greater proportion of these children was classified in the borderline/abnormal range than the children with GHD, although the difference was not significant. These results suggest that QoL is impaired in Japanese children due to short stature.

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